Azole compounds used as tuberculostatic and leishmanicide agents

ABSTRACT

This invention refers to new 1,2,3-triazole and imidazole compounds included in the families of compounds represented by general formula VIII. This invention also refers to a pharmaceutical composition comprising at least one of the azole compounds represented by the general formula VIII, to the use of such compositions and to methods of treatment or inhibition of tuberculosis and leishmaniasis.

This invention refers to azole compounds pertaining to the1,2,3-triazole and imidazole classes that can be used to treattuberculosis and leishmaniasis, with the advantage of having highactivity against microorganisms, more specifically against Mycobacteriumtuberculosis and protozoa of Leishmania gender, agents that cause thesediseases, as well as their salts, its stereoisomeric forms, racemicmixtures, pro-drugs, their metabolites; as well as pharmacologicalcompositions containing at least one of these compounds or their salt asan active principle and to the use of such compositions as drugs totreat or inhibit diseases.

Besides that, this invention also includes a treatment method orinhibition of tuberculosis and leishmaniasis, with the advantage ofpresenting a high activity against microorganisms, more specificallyagainst Mycobacterium tuberculosis and protozoa of the Leishmaniagender, comprising the administration of a pharmacologically effectivequantity of at least one of these compounds or their salt, to the livingbeing that needs the referred treatment or inhibition.

BACKGROUND OF INVENTION

Millions of persons in the world continue to die of diseases that can betreated, prevented or even inhibited. Inadequate or even non-existingtreatments to infectious and parasitic diseases are victimizing anelevated number or persons, especially in countries in development.Thousands of lives are lost or severely damaged due to these diseasesthat impact the social well-being and exclude an important parcel ofindividuals from their social and productivity activities.

Neglected diseases is the classification attributed to diseases that donot present a satisfactory treatment, do not create interest inpharmaceutical industries and, besides that, government funding isinsufficient to fight these kinds of diseases. Tuberculosis, HIV/Aidsand malaria are examples of neglected diseases, because although theyaffect individuals from developed countries, they mainly afflictpopulations of countries in development and they create only aperipheral interest from the pharmaceutical market. The lack ofinvestment from pharmaceutical industries in the development of newdrugs for certain diseases is directly connected to the low capacity ofpurchase of populations of countries in development.

The lack of interest, on the part of the pharmaceutical industries, forneglected diseases is so severe that within the period of 25 years, from1975 to 1999, from the 1.393 new drugs licensed, only 15 pertain to thisclass, 13 being for tropical diseases and 2 for tuberculosis.

The urgency on the discovery of new drugs for neglected and extremelyneglected diseases has motivated survey and development in severalcountries, including Brazil.

Tuberculosis (TB) is an infectious disease transmitted through theairway by a bacterium called Mycobacterium tuberculosis, also known asKoch bacillus in honor of the scientist Robert Koch, who isolated it in1882. There are several forms of tuberculosis (lung, meningeal,milliary, bone, renal, cutaneous, genital, etc), however, the mostfrequent form and the most contagious one is the pulmonary. A patientwith pulmonary tuberculosis, if not treated, can infect from 10 to 15persons in a year.

From reports of the presence of fragments of the bacillus in Egyptianmummies in 2400 B.C., tuberculosis presently infects approximately onethird of the world population and it is the main cause of death incountries in development. We estimate that 70% of the population indestitute countries is infected by the Koch bacillus, and every year,7.5 million new cases are reported and 2.8 million of deaths. The highrate of incidence of the disease in these is closely connected to theprecarious life conditions of the population. In India, for instance,which holds 15% of global populations, approximately 30% of thepopulation is infected by the M. tuberculosis and tuberculosis kills 14times more people than all tropical diseases.

Brazil, according to the World Health Organization (WHO), presents themost elevated number of cases of tuberculosis in Latin America, that is,62 new cases per 100.000 inhabitants, presently being the fourteenthamong the 23 countries responsible for 80% of the total cases oftuberculosis in the world. Sources from Health Ministry estimate aprevalence of 58/100.000 cases/inhabitants, within the country, withapproximately 111 mil new cases/year, and Rio de Janeiro being the statewith higher incidence and occurrence of approximately e 6.0 mildeaths/year from the disease.

HIV infection is one of the most significant risk factors known fortuberculosis infection.

It is estimated that one third of 42 million individuals infected by HIVare co-infected by M. tuberculosis and most of the persons infected byHIV develop TB as their first AIDS sign. Since HIV progressivelydestroys the immune system, there is a greater chance that virusinfected persons develop tuberculosis. This relation among epidemics isespecially concentrated in destitute countries. In Sub-Saharian Africa,for instance, approximately 50% of persons with HIV develop TB and onein three dies in consequence of the disease.

On the other hand, the increased number of multidrug-resistanttuberculosis (TBMR) has caused great concern, because it contributes toincrease the ration of deaths by TB, and being frequently associated toHIV infection.

Tuberculosis is a serious disease, but it is curable in practically 100%of new cases, as long as modern chemotherapy principles are followed,the adequate association of drugs and their regular use, for sufficienttime are the necessary means to avoid bacterial resistance andpersistence.

Chemotherapy for tuberculosis started during the 40's when the studiesabout tuberculostatic agents resulted in the discovery of several activesubstances face M. tuberculosis (Tripathi, R. P.; Tewari, N.; Dwivedi,N.; Tiwari, V. K.; “Fighting Tuberculosis: An Old Disease with NewChallenges”; Med. Res. Rev., 2005, 25, 1, 93-131). The presence ofmulti-resistant lineages reflects deficiencies in the control of TB,thus hindering treatment and prevention of the disease, causing itspropagation (Rossetti, M. L. R.; Valim, A. R. M.; Silva, M. S. N.;Rodrigues, V. S.; “Tuberculosis resistente: revisdo molecular”; Rev.Saúde Pública, 2002, 36, 525-32).

The first drug really active against tuberculosis, discovered by SelmanWalksman, in 1943, was streptomycin (SM) (Formula I where R═CHO) anaminoglycoside antibiotic insulated from the Streptomyces griseusbacterium. However, SM administered in higher doses can affect thecentral and peripheral nervous systems. Different synthetic by productsfrom streptomycin have been synthesized and have shown to be active astuberculostatic, such as, for example, dihydrostreptomycin (Formula Iwhere R═CH₂OH), which although demonstrates to be active can causeirreversible damage to the hearing system.

The p-amino-salicylic acid (PAS) (Formula II), first reported in 1946,presents great and selective activity against M. tuberculosis. It wasused combined to SM, but presently, according to WHO, its use isdirected to the multidrug-resistant tuberculosis treatment.

With progress of researches, new drugs have been introduced in therapy.Some of them are still used in treating tuberculosis, such isoniazide(INH) (Formula III), firstly used in 1952, and rifampicin (RMP) (FormulaIV), used as of 1967. These medicaments are still the basis of modernchemotherapy in treating the disease.

INH (Formula III) is active orally and besides exhibiting abacteriostatic action against the bacillus, it is highly active againstthe M. avium complex. Its minimum inhibitory concentration (MIC) is verylow (0.02-0.06 μg/mL) fact that contributes to its efficacy.

On the other hand, rifampicin (Formula IV, which is part of asemi-synthetic antibiotics group derived from rifamicin B, insulatedfrom Streptomyces mediterrani, is extremely effective against M.tuberculosis, with a MIC of 0.1 μg/mL to 1.0 μg/mL, and it presents aquick bactericide action in the elimination of persistent bacteria.

Due to its efficacy and ease administration, rifampicin (Formula IV) isthe drug chosen to treat patients co-infected by TB/HIV. However,rifampicin, as other by products of this class, presents a significantpharmaceutical interaction with several of the anti-retroviral,especially with protease inhibitors that have their concentrationdecreased by the inducing action of rifampicin.

Several compounds similar to INH have been synthesized and some haveshown activity against M. tuberculosis H37Rv. Among them ethionamide(Formula V) and a pyrazinamide (PZA) (Formula VI), which are also usedin TB chemotherapy.

Other significant drug used in treating tuberculosis, since 1968, isethambutol (EMB) (Figure VII) which is active against many variables ofMycobacterium. EMB is a synthetic amino alcohol, firstly synthesized in1960, with enantiomer as its stereo specific activity (Figure VII) withS,S configuration is the isomer that shows a tuberculostatic action, asthe enantiomer R,R presents an undesirable action, since it causesblindness.

Drugs used in the tuberculosis can be classified as first line andsecond line drugs. First line drugs are part of the TB primary treatmentplan and consist of the four medications previously mentionedisoniazide, rifampicin, pyrazinamide and ethambutol. The adequatetreatment of patients with combinations of these agents during longperiods (six to nine months) leads to cure in 95% of TB cases.

However, in cases with monotherapy, inadequate prescription, incorrectuse of the primary plan by the patient or even intolerance to first linedrugs can lead to failure in therapy and development of the M.tuberculosis strains resistant to one or more drugs. In this case,second line drugs are used.

Along with streptomycin (SM), p-amino salicylic acid and ethionamide,drugs used in the second chemotherapy plan are: Thiacetazone,D-cycloserine, clofazimine, terizidone, kanamycin and amicacin.

A significant class of antibiotics, fluoroquinolones, has been used inpulmonary, extrapulmonary and disseminated tuberculosis. These compoundswere approved by WHO as second line agents to TBMR treatment and areemployed in cases of resistance or intolerance to first line drugs.

Clinical studies have shown that during the first 48 hours of pulmonarytuberculosis ciprofloxacin and ofloxacin have demonstrated to be lesspotent than isoniazide. However, a gatifloxacin and moxifloxacin haveshown a greater activity in relation to INH. A fact that should bementioned is the non-existence of toxicity in ten patients submitted tosix months therapy with moxifloxacin, isoniazide and rifampicin. Due tothe high activity of the fluoroquinones as bactericides, severalclinical studies are being made in order to make them first line drugs.

Leishmaniasis depicts a complex of diseases with a significant clinicaland epidemiological diversity. Caused by approximately 20 species ofprotozoa of the Leishmania gender, it is transmitted to men by the stingof the female mosquito of the Phebotomine species in Europe and of theLutzomyia species in South and Central America.

The diseases present two clinical forms: integumental leishmaniasis andvisceral leishmaniasis. The Cutaneous Leishmaniasis (LC) is the mostcommon of the manifestations and it is characterized by ulcerativenodular lesions. The onset of lesions appears where the vector insectstung, thus being more frequent in body areas exposed, for instance,limbs and face. The incubation period between the sting and the onset ofthe lesion can vary from a few weeks to months. However, the cutaneousleishmaniasis disseminated (LCD) is characterized by multiple and smalllesions, with or without central ulceration, sometimes with an acneiformaspect. The diffuse form is a rare form of the disease detected in someof the Brazilian states, such as Maranhao, Para, Bahia and Mato Grosso.

The drugs presently recommended for the treatment of leishmaniasis(Croft, S. L.; Coombs, G. H.; “Leishmaniasis—current chemotherapy andrecent advances in the search for novel drugs” Trends Parasit., 2003,19, 502-508) are the pentavalent—the sodium stibogluconate (Pentostam®),the meglumine antimoniate(Glucantime®), the pentamidine and theamphotericin B and its three lipidic formulations—a liposomalamphotericin B, colloidal dispersion amphotericin B and a lipidiccomplex amphotericin B. Pentamidine was introduced in 1952 in therapyand even today it used as a third choice drug. Its use as aleishmanicide agent is restricted due to its high toxicity that cancause adverse effects such as nausea, vomiting, headache, hypoglycemiaand sudden death.

Due to increased cases of leishmaniasis and to long and inadequatetreatments with toxic drugs that are hard to be administered, thediscovery of new leishmanicide agents has become mandatory.

There is not, in all the extension of chemical, pharmacological andmedical literature, either in magazines, journals, encyclopedias, booksor patents, a quotation for the use of the 1,2,3-triazoles and imidazoleas tuberculostatic and leishmanicide agents, of potential use for thetreatment of tuberculosis and leishmaniasis.

ABSTRACT OF THE INVENTION

Considering the need to manufacture new drugs to treat and inhibittuberculosis and leishmaniasis new compounds 1,2,3-triazole andimidazole composed were developed, included in the family of thecompounds represented by the general formula VIII.

where:

-   X is an atom of “C” or “N”-   when X is “N” radicals of the triazole ring are represented by:-   R₁=COR₂, CSR₃, CN(R₄)R₅ or CF₂R₆;-   R₂=H, NHNH₂, alkyl, aryl substituted or not, OH, NR₇R₈ or OR₉-   R₃=alkyl or aryl substitute or not-   R₄=H, OH, alkyl or aryl substituted or not-   R₅=R₆=R₇=R₈=R₉=R₁₀=H, alkyl or aryl substituted or not-   when X is “C” radicals of the imidazole ring are represented by:-   R₁=COR₂-   R₂=NHNH₂, OH, OR₃, or NR₄R₅-   R₃=alkyl or aryl substituted or not-   R₄=R₅=H, alkyl or aryl substituted or not-   R₁₀=NHR₆ or NR₆R₇-   R₆=R₇=COR₈-   R₈=aryl substituted or not while radical R_(n) can be located in any    one or in more than one of the carbon atoms of the aromatic ring,    and these radicals can be equal or different, represented by    hydrogen, alkylic groups with 1 or more carbon atoms in a linear or    branched chain alkenes or alkynes, hydroxyl, hydroxyalkyl or    oxygenated functions in acyclic or cyclic systems forming an    heterocyclic ring, free or substituted amines, thioalkyl, donators    and/or removing groupings of electrons or halogens, thus “n” can    vary from 1 to 5.

Another objective of this invention refers to the pharmaceuticalcomposition comprising, as active principle, at least one of the1,2,3-triazole and/or imidazole compounds represented by the generalformula VIII.

Another objective of this invention is related to the use of suchcompositions as drugs to treat or inhibit tuberculosis andleishmaniasis.

Another objective of this invention refers to a method for treating orinhibiting tuberculosis and leishmaniasis.

The compounds 1,2,3-triazole and imidazole of formula VIII can be underthe form of salts, stereoisomeric forms, racemic mixtures, pro-drugs andmetabolites, and can be used as tuberculostatic and leishmanicideagents, to treat tuberculosis and leishmaniasis, with the advantage ofpresenting high activity against microorganisms.

DETAILED DESCRIPTION OF THE INVENTION

This invention refers to the new 1,2,3-triazole and imidazole compoundsincluded in the family of compounds represented by general formula VIII

where:

-   X is an atom of “C” or “N”-   when X is “N” the radicals of the triazole ring is represented by:-   R₁=COR₂, CSR₃, CN(R₄)R₅ or CF₂R₆;-   R₂=H, NHNH₂, alkyl, aryl substituted or not, OH, NR₇R₈ or OR₉-   R₃=alkyl or aryl substituted or not-   R₄=H, OH, alkyl or aryl substituted or not-   R₅=R₆=R₇=R₈=R₉=R₁₀=H, alkyl or aryl substituted or not-   when X is “C” the radicals of the imidazole ring are represented by:-   R₁=COR₂-   R₂=NHNH₂, OH, OR₃, or NR₄R₅-   R₃=alkyl or aryl substituted or not-   R₄=R₅=H, alkyl or aryl substituted or not-   R₁₀=NHR₆ or NR₆R₇-   R₆=R₇=COR₈-   R₈=aryl substituted or not    while radical R_(n) can be located in any one or in more than one of    the carbon atoms of the aromatic ring, and these radicals can be    equal or different, represented by hydrogen, alkylic groups with 1    or more carbon atoms in a linear or branched chain alkenes or    alkynes, hydroxyl, hydroxyalkyl or oxygenated functions in acyclic    or cyclic systems forming an heterocyclic ring, free or substituted    amines, thioalkyl, donators and/or removing groupings of electrons    or halogens, thus “n” can vary from 1 to 5.

In this invention all the compounds are presented as freebase orpharmaceutically accepted salts of them, preferably chlorides.

More particularly, compounds 1,2,3-triazole can be selected among:

-   4-carboxaldehyde-1-(4-chlorophenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(4-bromophenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(4-methylphenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(4-methoxyphenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(3-chlorophenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(3,5-dichlorophenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(3-cyanophenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(4-cyanophenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(4-nitrophenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(2-methoxyphenyl)-1H-1,2,3-triazole;-   4-carboxaldehyde-1-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole;-   1-(4-chlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(4-bromophenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(4-methylphenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(4-methoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(2,5-dimethoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(3-chlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(3,5-dichlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(3-cyanophenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(4-cyanophenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(4-nitrophenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(2-methoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   1-(3,4-dimethoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole;-   (AND)-4-chloride-N-((1-(4-chlorophenyl)-1H-1,2,3-triazole-4-il)methylene)benzenamine;    and,-   (E)-4-bromo-N-((1-(4-bromophenyl)-1H-1,2,3-triazole-4-il)    methylene)benzenamine    which are 1,2,3-triazole compounds or a pharmaceutical accepted salt    of it, preferably chloride, combined with a pharmaceutically    acceptable vehicle.

Compounds 1,2,3-triazole presented in this invention can be synthesizedaccording to processes known by experts in this area, as described inarticles “Arnold, Z.; {hacek over (S)}auliová, J.; Krch{hacek over(n)}ák, V.; Synthetic Reactions of Dimethylformamide. XXVII. A SimpleSynthesis of Aminomalonaldehyde Derivatives, Coll. Czec. Chem. Commun.,1973, 38, 2633-2640”; and, “Arnold, Z.; {hacek over (S)}auliová, J.;Synthetic Reactions of Dimethylformamide. XXVIII. Diazomalonaldehyde;Coll. Czec. Chem. Commun., 1973, 38, 2641-2647”, but always observingthe balance of their intrinsic lipophilic and hydrophiliccharacteristics, because it influences the antimicrobial leishmanicideactivity.

With reference to imidazole compounds they can be preferably selectedamong:

-   Ester    5-[(bis(4-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate    of ethyl;-   Ethyl Ester    5-[(bis(4-fluorobenzoic)amino]-1-(4-cyanophenyl)-1H-imidazole-4-carboxylate;-   Ethyl Ester    5-[(bis(4-fluorobenzoic)amino]-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate;-   Ethyl Ester    5-[(bis(4-fluorobenzoic)amino]-1-(3,5-dichloridephe-nyl)-1H-imidazole-4-carboxylate;-   Ethyl Ester    5-[(bis(4-fluorobenzoic)amino]-1-(2,6-difluorophe-nyl)-1H-imidazole-4-carboxylate;-   Ethyl Ester    5-[(bis(2-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate;-   Ethyl Ester    5-[(bis(2-fluorobenzoic)amino]-1-(4-cyanophenyl)-1H-imidazole-4-carboxylate;-   Ethyl Ester    5-[(bis(2-fluorobenzoic)amino]-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate;-   Ethyl Ester    5-[(bis(2-fluorobenzoic)amino]-1-(3,5-dichloridephe-nyl)-1H-imidazole-4-carboxylate;-   Ethyl    5-[(bis(2-fluorobenzoic)amino]-1-(2,6-difluorophe-nyl)-1H-imidazole-4-carboxylate;-   Ethyl Ester    5-[(4-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate;-   Ethyl Ester    1-(4-cyanophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate;-   Ethyl Ester    1-(4-chlorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate;-   Ethyl Ester    1-(3,5-dichlorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate;-   Ethyl ester    1-(2,6-difluorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate;-   Ethyl Ester    5-[(2-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate;-   Ethyl Ester    1-(4-cyanophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate;-   Ethyl Ester    1-(4-chlorophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate;-   Ethyl Ester    1-(3,5-dichlorophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate;    and,-   Ethyl Ester    1-(2,6-difluorophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate.

Imidazole compounds presented in this invention can be synthesizedaccording to processes known by experts in this area, as described inarticles “Wamhoff, H.; Berressem, R.; Herrmann, S.; Heterocyclisheβ-Enaminoester; 55. Imidazo[4,5-d]-, Thiazolo[5,4-d]-undThiazolo[4,5-d][1,3] oxazinone; Synthesis, 1993, 107-111” and “Jakobsen,Palle; Horneman, A. M.; Persson, AND.; Inhibitors of the TissueFactor/Factor VIIa-Induced Coagulation: Synthesis and In VitroEvaluation of Novel 2-Aryl-Substituted Pyrido[3,4-d][1,3]-,Pyrido[2,3-d][1,3]-, Pyrazino[2,3-d][1,3]-, Pyrimido[4,5-d][1,3],Pyrazolo[4,5-d][1,3]-, Thieno[2,3-d][1,3]-, andThieno[2,3-d][1,3]-,oxazin-4-ones; Bioorg. Med. Chem.; 2000, 8,2803-2812” but always observing the balance of their intrinsiclipophilic and hydrophilic characteristics, because it influences theantimicrobial and leishmanicide activity.

Pharmaceutical compounds containing at least one 1,2,3-triazole and/orimidazole compounds of this invention, or a salt of it, can beadministered in the pharmaceutical form of solution, suspension,emulsion, ointment, cream, gel, tablet or capsule, oral, injection ortopic use, prepared as of powder, solution or suspension of at least oneof the compounds in an adequate concentration, and in a vehiclepharmaceutically acceptable, in order to create the adequate dosageform. These compositions are employed in the treatment or inhibition oftuberculosis and leishmaniasis.

BRIEF DESCRIPTION OF FIGURES

In order to enable a better understanding of the invention, below, wehave listed the figures with a brief description of them.

In Figures, compounds were represented by codes, and the correlationamong them is listed on Table 1:

TABLE 1 Correlation among compounds and codes Compounds Code

114a

114j

121a

121j

FIG. 1—Essay of antimicrobial activity of compounds 1,2,3-triazole typeI and II

FIG. 2—Spectrum of proton RMN of derivatives 1,2,3-triazole 114i (typeI) and 121i (type II).

FIG. 3—Spectrum of proton RMN derivatives 1,2,3-triazole 119 (type III).

FIG. 4—Spectrum of proton RMN derivatives imidazole 145d(di-substituted) and 149d (mono-substituted).

DETAILED DESCRIPTION OF INVENTION

This invention is described in detail through examples presented asfollows. It is necessary to emphasize that the invention is not limitedto these examples, but it also includes several variations andmodifications within the limits within which it acts.

EXAMPLE 1

A—Pharmacological evaluation of the triazole derivatives of type I(Formula IX) and II (Formula X)

A.1—Antimicrobial Activity

Type I and II 1,2,3-triazole derivatives were submitted to a primarybiological evaluation, in vitro, regarding the inhibitory activity ofthe Mycobacterium tuberculosis H37Rv (ATCC-27294).

The definition of minimum inhibitory concentrations (MIC) of substances,that is, the smallest concentration of the compound in which bacterialgrowth is not observed, was made using the colorimetric method known asMABA (Microplate Alamar Blue Assay). This method consists in an essayperformed by the micro dilution in plates, using, as cell growthindicator, the Alamar Blue® indicator pigment, which is afluorescent/colorimetric indicator with redox property. The oxidizedform is blue (non-fluorescent) and indicates the absence of bacterialgrowth. The reduced form presents a pink color (fluorescent), indicatesthe proliferation of bacteria. This methodology has been applied todetermine the resistance profile of microbacteria to antimicrobials(FIG. I).

To perform the essay, sterile micro plates with 96 wells were used in away that each wells presented a total of 200 μL of a mixture composed bythe adequate culture mean, of the compound to be tested and of thebacterial suspension. The comparison pattern used was rifampicin, whichpresents a MIC equal to 1.0 μg/mL.

After 5 incubation days, 15 μL of Alamar Blue® was added to each welland microplates were incubated for more than 24 hours at 37° C. At theend of this period of time, the change of color in each well wasobserved, and MIC was defined as the smallest concentration of thecompound that delimitates the change from blue to pink.

Thus, the antimicrobial activity essay of compounds 114a, 121a, 114j and121j was performed, observing that the same were able to inhibitbacterial growth. As can be seen in FIG. 1, compounds presented MIC of 5μg/mL, 40 μg/mL, 20 μg/mL and 40 μg/mL, respectively.

The other compounds in this series were evaluated and Table 2 shows thevalues defined for MIC, in μg/mL, and the inhibition percentagepresented by each substance.

TABLE 2 Antimicrobial activity of type I and II compounds against M.tuberculosis H37Rv (ATCC 27294) MIC Data and inhibition percentage TypeMIC Inhibition Type MIC Inhibition R I (μg/mL) (%) II (μg/mL) (%) 4-Cl114a 5.0  na* 121a 40.0 nd 4-Br 114b 5.0 100 121b 20.0 75 4-CH₃ 114c 2.5100 121c 40.0 87 4-OCH₃ 114d 10.0 100 121d 10.0 93 2,5-di (OCH₃) 114e80.0 59 121e 80.0 74 3-Cl 114f 10.0 100 121f 80.0 54 3,5-di (Cl) 114g2.5 na 121g 80.0 55 3-CN 114h 20.0 na 121h 80.0 na 4-CN 114i 5.0 na 121i20.0 na 4-NO₂ 114j 20.0 na 121j 40.0 na 2-OCH₃ 114l 40.0 94 121l 40.0 863,4-di (OCH₃) 114m 80.0 na 121m 80.0 66 Rifampicin 1.0 1.0 *na = notavailable

Among 4-carboxaldehydes derivatives, the most effective were 114c(R=4-CH₃) derivatives and 114g (R=3,5-di(Cl), which showed a MIC equalto 2.5 μg/mL followed by compounds 114a (R=4-Cl), 114b (R=4-Br) and 114i(R=4-CN) with MIC equal to 5.0 μg/mL. These values of MIC are inferiorto the value of 6.25 μg/mL postulated by Global Discovery Program forNovel Anti-tuberculosis Drugs as limiting in the evaluation of newprospects to inhibit M. tuberculosis.

A.2—Leishmanicide Evaluation

The evaluation of the Leishmanicide activity of the type I and II1,2,3-triazole derivatives was made through in vitro essays againstpromastigote forms of Leishmania amazonensis, and after the incubationwith compounds, live parasites are counted by fluorescence, thusobtaining as a result, the percentage of inhibition of the compoundsevaluated.

Essays were performed in triplicate using pentamidine as a positivepattern with a 160 μg/mL concentration. Table shows us the resultsobtained for 114f, 114j, 121f and 121l derivatives.

TABLE 3 Percentage of parasitic inhibition Compounds                  Concentration (μg/mL)          

 

 

320 72% No inhibition 160 53% No 11% No inhibition inhibition 80 Noinhibition No No No inhibition inhibition inhibition 20 No inhibition Noinhibition No No inhibition inhibition inhibition 10 No inhibition No No93% No inhibition inhibition inhibition 5 No inhibition No No No Noinhibition inhibition inhibition inhibition

Compared to pentamidine, which in a 160 μg/mL concentration presents aninhibition percentage of 53%, with the most active compound, thegem-difluormethyl 121f derivative with an inhibition percentage of 93%in a 10.0 μg/mL concentration. 114f derivative, precursor of 121f, alsopresented activity against the promastigote forms, with an inhibitionpercentage of 72%, however in a concentration superior to the pattern(pentamidine). However, derivative 114j presented an inhibitionpercentage 11% lower than pentamidine with the same 160.0 μg/mLconcentration and o 121l did not present activity against the protozoa.

The evaluation of preliminary results suggests the presence of thechloride in 121f and 114f can be associated to the activity shown byboth compounds and to the fact that the change of the aldehyde groupinto gem-difluormethylenic originated an increase of the leishmanicideactivity.

B—Antimicrobial Evaluation of the Type III Triazole Derivatives

The antimicrobial activity of type III 1,2,3-triazole derivatives(Formula XI) was evaluated.

-   for example,-   R=Cl-   (AND)-4-chloride-N-((1-(4-chlorophenyl)-1H-1,2,3-triazole-4-il)methylene)benzenamine;    and,-   R=Br-   (AND)-4-bromo-N-((1-(4-bromophenyl)-1H-1,2,3-triazole-4-il)    methylene)benzenamine    which have shown an inhibitory activity of the tuberculosis    presenting a MIC of 40 μg/mL and 20 μg/mL, respectively.

Thus, three classes of compounds derived from the 1,2,3-triazole nucleuswhich presented high inhibitory activity in vitro, of M. tuberculosisH37Rv (ATCC 27294). These results, even being preliminary, theevaluation indicates that the derivatives of the 1,2,3-triazole nucleusare promising tuberculostatic agents.

EXAMPLE 2

Below there is the detailed description of the obtainment of both type Iand II 1,2,3-triazole compounds, which were confirmed by analyticalmethods represented by Figure II.

A—Method of general obtainment of type I 1,2,3-triazole derivatives:

(Translation: Diazomalonaldehyde)

In a balloon containing 5 mmol of diazomalonaldehyde 30.0 mL ofdistilled water was added. Then, a recently prepared solution with 4.5mmol of the chloride derivative of the desired amine was added slowlyinto 5 mL of distilled water. The reaction mixture was under disturbanceat room temperature, for 4 hours, and the precipitation of triazoleproduct was observed. The solid was insulated by filtration and washedwith ice water.

This methodology was used to obtain the below mentioned compounds:

a—4-carboxaldehyde-1-(4-chlorophenyl)-1H-1,2,3-triazole (114a)

The derivate (114a) was prepared with 75.0% of output, as of thereaction of the diazomalonaldehyde with the 4-chloroaniline chloride,thus obtaining an amorphous white solid with fusion point at159.0-161.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 7.56 (d, 2H, H3′ and H5′,J=1.5 and 3.0 Hz); 7.74 (d, 2H, H2′ and H6′, J=7.0 Hz); 8.53 (s, 1H,H5); 10.22 (s, 1H, CHO);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 122.0 (C3′ and C5′); 123.0(C5); 130.2 (C2′ and C6′); 134.6 (C1′); 135.8 (C4′); 148.2 (C4); 184.9(CHO);

IV (KBr) cm⁻¹: 3094 (ν C—H_(ar)); 2842 (νC—H_(aldehyde)); 1705 (ν C═O);

EM (m/z): 207 (M⁺; 32%); 178 (M⁺−29; 100%); 151 (M⁺−56; 75%); 111(M⁺−96; 86%); 89 (M⁺−118; 35%); 75 (M⁺−132; 84%);

Elementary Analysis (theoretical/experimental):

-   -   C—52.05%/52.37%;    -   H—2.91%/2.76%;    -   N—20.24%/20.64%.

b—4-carboxaldehyde-1-(4-bromophenyl)-1H-1,2,3-triazole (114b)

The derivative (114b) was prepared with 76.0% of output, as of thereaction of the diazomalonaldehyde with the 4-bromoaniline chloride,thus obtaining an amorphous white solid with fusion point at190.0-191.0° C.

RMN de ¹H (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 7.68 (d, 2H, H3′ and H5′,J=9.0 Hz); 7.72 (d, 2H, H2′ and H6′, J=9.0 Hz); 8.54 (s, 1H, H5); 10.22(s, 1H, CHO);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 122.2 (C2′ and C6′); 122.9(C5); 123.7 (C4′); 133.2 (C3′ and C5′); 135.1 (C1′); 148.2 (C4); 184.9(CHO);

IV (KBr) cm⁻¹: 3098 (ν C—H_(ar)); 2851 (ν C—H_(aldehyde)); 1698 (ν C═O);

EM (m/z): 253 (M⁺; 11%); 224 (M⁺−29; 32%); 197 (M⁺−56; 18%); 157 (M⁺−96;42%); 116 (M⁺−137; 100%);

Elementary Analysis (theoretical/experimental):

-   -   C—42.88%/42.77%;    -   H—2.40%/2.36%;    -   N—16.67%/16.90%.

c—4-carboxaldehyde-1-(4-methylphenyl)-1H-1,2,3-triazole (114c)

The derivative (114c) was prepared with 86.0% of output, as of thereaction of the diazomalonaldehyde with 4-methylaniline chloride, thusobtaining an amorphous white solid with fusion point at 105.0-106.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 2.45 (s, 1H, CH₃); 7.36 (d,2H, H3′ and H5′, J=8.0 Hz); 7.64 (d, 2H, H2′ and H6′, J=8.0 Hz); 8.49(s, 1H, H5); 10.22 (s, 1H, CHO);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 21.1 (CH₃); 140.1 (C1′); 133.8(C4′); 130.5 (C2′ and C6′); 123.0 (C5); 120.7 (C3′ and C5′); 148.0 (C4);185.1 (CHO);

IV (KBr) cm⁻¹: 3136 (ν C—H_(ar)); 2842 (ν C—H_(aldehyde)); 1696, (νC═O);

EM (m/z): 187 (M⁺; 20%); 158 (M⁺−29; 52%); 130 (M⁺−57; 100%); 91 (M⁺−96;62%).

Elementary Analysis (theoretical/experimental):

-   -   C—64.16%/65.10%;    -   H—4.85%/4.65%;    -   N—22.45%/22.24%.

d—4-carboxaldehyde-1-(4-methoxyphenyl)-1H-1,2,3-triazole (114d)

The derivative (114d) was prepared with 76.0% of output, as of thereaction of the diazomalonaldehyde with the 4-metoxyaniline chloride,thus obtaining an amorphous white solid with fusion point at 158.6-161°C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 3.89 (s, 3H, OCH₃); 7.06(ddd, 2H, H3′ and H5′, J=4.5 and 9.0 Hz); 7.66 (ddd, 2H, H2′ and H6′,J=4.5 and 9.0 Hz); 8.46 (s, 1H, H5); 10.21 (s, 1H, CHO);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 55.7 (OCH3); 123.0 (C5); 129.4(C1′); 122.4 (C2′ and C6′), 115.0 (C3′ and C5′); 148.5 (C4); 160.5(C4′); 185.1 (CHO);

IV (KBr) cm⁻¹: 3133 (ν C—H); 2839 (ν C—H_(aldehyde)); 1692 (ν C═O);

EM (m/z): 203 (M⁺; 39.5%); 174 (M⁺−29; 40%); 160 (M⁺−43; 79.3%); 146(M⁺−57; 42.3%); 132 (M⁺−71; 100%); 77 (M⁺−126; 40%);

Elementary Analysis (theoretical/experimental):

-   -   C—59.11%/59.55%;    -   H—4.43%/4.86%;    -   N—20.69%/20.42%.

e—4-carboxaldehyde-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole (114e)

The derivative (114e) was prepared with 73.0% of output, as of thereaction of diazomalonaldehyde with the 2,5-dimethoxyaniline chloride(114e), thus obtaining an amorphous yellow solid with fusion point at89.3-89.8° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 3.85 (s, 3H, OCH ₃); 3.88 (s,3H, OCH ₃); 7.01 (dd, 1H, H4′, J=3 and 9 Hz); 7.06 (d, 1H, H3′, J=9 Hz);7.49 (d, 1H, H6′, J=3 and 9 Hz); 8.79 (s, 1H, H5); 10.23 (s, 1H, CHO);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 55.7 (OCH3); 123.0 (C5); 129.4(C1′); 122.4 (C2′ and C6′), 115.0 (C3′ and C5′); 148.5 (C4); 160.5(C4′); 185.1 (CHO);

IV (KBr) cm⁻¹: 3369 (ν C—H); 2929 (ν C—H_(aldehyde)); 1697 (ν C═O); 1228(νC—O);

EM (m/z): 233 (M⁺; 45.0%); 204 (M⁺−29; 40%); 190 (M⁺−43; 38.4%); 176(M⁺−57; 27.8%); 162 (M⁺−71; 100%);

Elementary Analysis (theoretical/experimental):

-   -   C—56.65%/56.63%;    -   H—4.75%/5.56%;    -   N—18.02%/17.40%.

f—4-carboxaldehyde-1-(3-chlorophenyl)-1H-1,2,3-triazole (114f)

The derivative (114f) was prepared with 73.0% of output, as of thereaction of diazomalonaldehyde with the 3-chlorideaniline chloride, thusobtaining an amorphous yellow solid with fusion point at 129.4-130.5° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 7.51 (m, 2H, H4′ and H6′,J=1.5; 3.0 and 8.0 Hz); 7.85 (t, 1H, H2′, J=1.5 and 3.0 Hz); 7.68 (ddd,1H, H5′, J=1.5; 3.0 and 8.0 Hz); 8.55 (s, 1H, H5); 10.23 (s, 1H, CHO);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 118.8 (C6′); 121.2 (C2′);123.0 (C4′); 129.5 (C5); 131.1 (C5′); 135.9(C1′); 136.9 (C3′); 148.2(C4); 184.8 (CHO);

IV (KBr) cm⁻¹: 3127 (ν C—H); 2874 (ν C—H_(aldehyde)); 1701 (ν C═O);

EM (m/z): 207 (M⁺; 18%); 178 (M⁺−29; 92%); 151 (M⁺−56; 40%); 111 (M⁺−96;100%); 89 (M⁺−118; 38%); 75 (M⁺−132; 92%);

Elementary Analysis (theoretical/experimental):

-   -   C—52.05%/52.37%;    -   H—2.91%/2.76%;    -   N—20.24%/20.64%.

g—4-carboxaldehyde-1-(3,5-dichlorophenyl)-1H-1,2,3-triazole (114g)

The derivative (114g) was prepared with 73.0% of output, as of thereaction of diazomalonaldehyde with the 3,5-dichlorideaniline chloride,thus obtaining an amorphous white solid with fusion point at156.0-157.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 7.52 (d, 1H, H4′, J=1.5 Hz);7.75 (d, 2H, H2′ and H6′ J=1.5 Hz); 8.75 (s, 1H, H5); 10.22 (s, 1H,CHO);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 119.3 (C2′ and C6′); 123.0(C4′); 129.83 (C5); 136.6 (C1′); 137.3 (C4); 148.3 (C3′ and C5′); 184.6(CHO);

IV (KBr) cm⁻¹: 3126 (ν C—H); 3085 (ν C—H_(aldehyde)); 1690 (ν C═O);

EM (m/z): 241 (M⁺; 18%); 212 (M⁺−29; 100%); 145 (M⁺−96; 50%); 109(M⁺−132; 42%);

Elementary Analysis (theoretical/experimental):

-   -   C—44.66%/44.91%;    -   H—2.08%/2.19%;    -   N—17.36%/16.70%.

h—4-carboxaldehyde-1-(3-cyanophenyl)-1H-1,2,3-triazole (114h)

The derivative (114h) was prepared with 80.0% of output, as of thereaction of diazomalonaldehyde with the chloride of 3-cyanoaniline, thusobtaining an amorphous white solid with fusion point at 177.7-179.8° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 7.75 (t, 1H, H5′, J=8 Hz, 0.5Hz); 8.06 (ddd, 1H, H6′, J=1, 2 and 8 Hz); 7.84 (dt, 1H, H4′, J=1 and 8Hz); 8.15 (t, 1H, H2′, J=2 Hz); 8.61 (s, 1H, H5); 10.24 (s, 1H, CHO);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 114.6 (C3′); 117.0 (CN); 124.7(C5); 133.1 (C5′); 124.1 (C2′); 131.2 (C6′); 122.9 (C4′); 136.7 (C1′);148.0 (C4); 184.6 (CHO);

IV (KBr) cm⁻¹: 3130 (ν C—H); 2839 (ν C—H_(aldehyde)); 2234 (ν CN); 1697(ν C═O);

EM (m/z): 198 (M⁺; 9%); 212 (M⁺−29; 100%); 142 (M⁺−56; 40%); 115 (M⁺−83;94%); 102 (M⁺−96; 42%);

Elementary Analysis (theoretical/experimental):

-   -   C—60.60%/60.72%;    -   H—3.05%/3.32%;    -   N—28.27%/28.15%.

i—4-carboxaldehyde-1-(4-cyanophenyl)-1H-1,2,3-triazole (114i)

The derivative (114i) was prepared with 75.0% of output, as of thereaction of diazomalonaldehyde with the 4-cyanoaniline chloride, thusobtaining an amorphous white solid with fusion point at 178.9-179.6° C.

¹H RMN (500.00 MHz; DMSO_(d6)/Me₄Si; δ (ppm)): 8.14 (d, 2H, H3′ and H5′,J=9 Hz); 8.24 (d, 2H, H2′ and H6′, J=9 Hz); 9.71 (s, 1H, H5); 10.14 (s,1H, CHO);

¹³C RMN (125.0 MHz, DMSO_(d6)/Me₄Si; δ(ppm)): 111.8 (C4′); 117.8 (CN);126.4 (C5); 121.1 (C2′ and C6′); 134.2 (C3′ and C5′); 138.8 (C1′);1473.6 (C4); 184.6 (CHO);

IV (KBr) cm⁻¹: 3116 (ν C—H); 2865 (ν C—H_(aldehyde)); 2232 (ν CN); 1697(ν C═O);

EM (m/z): 198 (M⁺; 10%); 169 (M⁺−29; 96%); 142 (M⁺−56; 48%); 115 (M⁺−83;40%); 102 (M⁺−96; 100%);

Elementary Analysis (theoretical/experimental):

-   -   C—60.60%/60.32%;    -   H—3.05%/3.16%;    -   N—28.27%/28.66%.

j—4-carboxaldehyde-1-(4-nitrophenyl)-1H-1,2,3-triazole (114j)

The derivative (114j) was prepared with 80.0% of output, as of thereaction of diazomalonaldehyde with the 4-nitroaniline chloride (114j),thus obtaining an amorphous yellow solid with fusion point at185.0-186.0° C.

¹H RMN (500.00 MHz; DMSO_(d6)/Me₄Si; δ (ppm)): 8.31 (d, 2H, H2′ and H6′,J=8.8 Hz); 8.48 (d, 2H, H3′ and H5′, J=8.8 Hz); 9.78 (s, 1H, H5); 10.15(s, 1H, CHO);

¹³C RMN (125.0 MHz, DMSO_(d6)/Me₄Si; δ (ppm)): 121.4 (C2′ and C6′);125.4 (C3′ and C5′); 126.7 (C5); 140.2 (C4); 147.2 (C1′); 147.7 (C4′);184.8 (CHO);

IV (KBr) cm⁻¹: 3136.18 (ν C—H_(ar)); 1696.21 (νC═O); 1524.18 (νNO₂);1348.96 (νNO₂); 856.83 (νN═O); 785 (νN═O);

EM (m/z): 218 (M⁺; 9%); 189 (M⁺−29; 100%); 143 (M⁺−75; 60%); 116(M⁺−102; 52%);

Elementary Analysis (theoretical/experimental):

-   -   C—49.55%/49.91%;    -   H—2.77%/2.94%;    -   N—25.68%/25.60%.

l—4-carboxaldehyde-1-(2-methoxyphenyl)-1H-1,2,3-triazole (114l)

The derivative (114l) was prepared with 66.0% of output, as of thereaction of diazomalonaldehyde with the 2-methoxyaniline chloride, thusobtaining an amorphous yellowish solid with fusion point at 108.0-109.5°C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 3.93 (s, 3H, OCH ₃); 7.15 (m,2H, H4′ and H5′, J=1.0; 6.5 and 8.0 Hz); 7.47 (ddd, 1H, H3′, J=1.5 and8.0 Hz); 7.87 (dd, 1H, H6′, J=1.5; 6.5 and 8.0 Hz); 8.72 (s, 1H, H5);10.24 (s, 1H, CHO);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 56.0 (OCH ₃); 112.3 (C3′);125.2 (C1′ and C6′); 121.3 (C5′); 130.9 (C4′); 127.3 (C5); 147.3 (C4);150.8 (C2′); 185.3 (CHO);

IV (KBr) cm⁻¹: 3157 (ν C—H); 2979 (ν C—H_(aldehyde)); 1685 (ν C═O);

EM (m/z): 203 (M⁺; 38%); 174 (M⁺−29; 30%); 160 (M⁺−43; 60%); 146 (M⁺−57;72%); 104 (M⁺−99; 70%); 77 (M⁺−126; 100%);

Elementary Analysis (theoretical/experimental):

-   -   C—59.11%/58.62%;    -   H—4.43%/4.56%;    -   N—20.69%/20.38%.

m—4-carboxaldehyde 1-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole (114m)

The derivative (114m) was prepared with 80.0% of output, as of thereaction of diazomalonaldehyde with the 3,4-dimethoxyaniline chloride,thus obtaining an amorphous yellow solid with fusion point at170.0-171.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 3.96 (s, 3H, OCH ₃); 3.98 (s,3H, OCH₃); 6.99 (d, 1H, H5′, J=8.5 Hz); 7.23 (dd, 1H, H2′, J=2.5 and 8.5Hz); 7.36 (d, 1H, H2′, J=2.5 Hz); 8.49 (s, 1H, H5); 10.21 (s, 1H, CHO);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 56.2 (3′ or 4′-OCH₃); 56.3 (3′or 4′-OCH₃); 105.0 (C2′); 111.2 (C5′); 112.8 (C6′); 129.5 (C1′); 123.1(C5); 148.0 (C4); 149.9 (C4′); 150.1 (C3′); 185.1 (CHO);

IV (KBr) cm⁻¹: 3131 (ν C—H); 2970 (ν C—H_(aldehyde)); 1693 (ν C═O);

EM (m/z): 233 (M⁺; 50%); 204 (M⁺−29; 9%); 190 (M⁺−43; 80%); 176 (M⁺−57;30%); 162 (M⁺−71; 100%);

Elementary Analysis (theoretical/experimental):

-   -   C—56.55%/55.95%;    -   H—4.72%/4.96%;    -   N—18.02%/17.88%.        B. General Method of Obtainment of Type II 1,2,3-Triazole        Derivatives

Translation: Type I Type II

In a 50 mL volumetric flask, 7.5 mmol of the derivative 4-carboxaldehydetriazole and 15.0 mL of dry dichloromethane was added. After completedissolution of the starting compound, 15.0 mmol of DAST was slowlyadded, at room temperature. The resulting reaction mixture was shaken atroom temperature and followed-up by c.c.f., using ethyl hexane/acetate(7:3) as eluant, and after approximately two hours of reaction, therewas the complete consume of the starting material. The reaction mixturewas poured out in 20.0 mL of an iced solution of sodium bicarbonate andextracted with dichloromethane (3×15 mL). Organic stages were combinedand washed with a saturated solution of sodium chloride (2×10.0 mL) anddistilled water (2×10.0 mL). The organic stage was dried out withanhydrous sodium sulfate and the solvent evaporated in vacuum. Theresidue obtained was purified by a chromatographic column usingchloroform as eluant.

This methodology was employed to obtain of the below mentionedcompounds:

a—1-(4-chlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole (121a)

The derivative 121a was prepared with 95.0% of output, as of thereaction of fluoridation of the derivative4-carboxaldehyde-1-(4-chlorophenyl)-1H-1,2,3-triazole (114a) with thediethylamino sulphur trifluoride, DAST, obtaining a white solid withfusion point of 122.0-124.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 6.95 (t, 1H, CF₂ H, J=54.5Hz); 7.71 (d, 2H, H3′ and H5′, J=7.0 Hz); 7.54 (d, 2H, H2′ and H6′,J=7.0 Hz); 8.21 (s, 1H, H5);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ (ppm)): 109.9 (t, CF₂H, J=236.5 Hz);120.5 (C5); 134.9 (C1′); 135.4 (C4′); 122.0(C2′ and C6′); 130.1 (C3′ andC5′); 143.7 (t, C4, J=28.1 Hz);

¹⁹F RMN (376.0 MHz, CDCl₃/CFCl₃; δ (ppm)): −112.5 (2F, CHF₂);

IV (KBr) cm⁻¹: 3150 (ν C—H); 1046 (ν C—F);

EM (m/z): 229 (M⁺; 60%); 220 (M⁺−29; 68%); 182 (M⁺−47; 80%); 137 (M⁺−92;67%); 111 (M⁺−118; 100%); 75 (M⁺−154; 90%),

Elementary Analysis (theoretical/experimental):

-   C—47.08%/47.62%;-   H—2.63%/3.30%;-   N—18.30%/16.02%.

b—1-(4-bromophenyl)-4-difluoromethyl-1H-1,2,3-triazole (121b)

The derivative 121b was prepared with 95.0% of output, as of thereaction of the fluoridation of the derivative4-carboxaldehyde-1-(4-bromophenyl)-1H-1,2,3-triazole (114b) with thediethylamino sulphur trifluoride, DAST, thus obtaining a white solidwith fusion point at 141.0-144.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 6.94 (t, 1H, CF₂ H, J=68.0Hz); 7.64 (d, 2H, H3′ and H5′, J=11.0 Hz); 7.69 (d, 2H, H2′ and H6′,J=11.0 Hz); 8.20 (s, 1H, H5).

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ (ppm)): 109.5 (t, CF₂H, J=233.2 Hz);120.4 (C5); 135.5 (C1′); 122.2 (C3′ and C5′); 133.6 (C4′); 133.1 (C2′and C6′); 143.7 (t, C4, J=28.5 Hz).

¹⁹F RMN (376.0 MHz, CDCl₃/CFCl₃; δ (ppm)): −112.5 (2F, CHF₂);

IV (KBr) cm⁻¹: 1497 (δ C-Har); 1043 (ν C—F);

EM (m/z): 273 (M⁺; 85%); 245 (M⁺−28; 33%); 226 (M⁺−49; 60%); 181 (M⁺−94;50%); 154 (M⁺−119; 83%); 166 (M⁺−109; 100%);

Elementary Analysis (theoretical/experimental):

-   C—39.44%/39.66%;-   H—2.04%/2.14%;-   N—15.33%/15.16%.

c—1-(4-methylphenyl)-4-difluoromethyl-1H-1,2,3-triazole (121c)

The derivative (121c) was prepared with 93.0% of output, as of thereaction of fluoridation of the derivative4-carboxaldehyde-1-(4-methylphenyl)-1H-1,2,3-triazole (114c) with thediethylamino sulphur trifluoride DAST, thus obtaining a white solid withfusion point at 96.5-97.5° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 2.43 (s, 1H, CH₃); 6.94 (t,1H, CF₂ H, J=54.5 Hz) 7.31 (d, 2H, H3′ and H5′, J=8.8 Hz); 7.60 (d, 2H,H2′ and H6′, J=8.8 Hz); 8.18 (s, 1H, H5);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ (ppm)): 20.5 (CH₃); 109.5 (t, CF₂H,J=233.4 Hz); 119.9 (C5); 139.1 (C1′); 133.6 (C4′); 129.8 (C2′ and C6′);120.1 (C3′ and C5′); 142.7 (t, C4, J=28.5 Hz);

¹⁹F RMN (376.0 MHz, CDCl₃/CFCl₃; δ (ppm)): −112.3 (2F, CHF₂);

IV (KBr) cm⁻¹: 3162 (ν C—H); 1031 (ν C—F);

EM (m/z): 209 (M⁺; 42%); 180 (M⁺−29; 68%); 162 (M⁺−47; 40%); 130 (M⁺−79;42%); 91 (M⁺−118; 100%);

Elementary Analysis (theoretical/experimental):

-   C—57.41%/57.83%;-   H—4.34%/4.54%;-   N—20.09%/19.97%.

d—1-(4-methoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole (121d)

The derivative 121d was prepared with 97.0% of output, as of thefluoridation reaction to the derivative4-carboxaldehyde-1-(4-methoxyphenyl)-1H-1,2,3-triazole (114d) with thediethylamino sulphur trifluoride, DAST, thus obtaining a white solidwith fusion point at 98.2-100.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 3.89 (s, 3H, 2′ OCH₃); 6.95(t, 1H, CHF₂, J=55.0 Hz); 7.04 (dd; 2H, H3′ and H5′; J=2.0 and 7.0 Hz);7.63 (dd, 2H, H2′ and H6′, J=2.0 and 7.0 Hz); 8.14 (s1, 1H, H5);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ (ppm)): 55.6 (3H, OCH₃); 110.1 (t,CHF₂, J=234.7 Hz); 115.0 (C3′ and C5′); 120.6 (C5); 122.5 (C2′ and C6′);160.3 (C4′); 129.8 (C1′); 143.2 (t, C4, J=29.1 Hz);

¹⁹F RMN (376.0 MHz, CDCl₃/CFCl₃; δ (ppm)): −112.2 (2F, CHF₂);

IV (KBr) cm⁻¹: 3097 (ν C—H); 1051 (ν C—F); 1023 (ν C—O);

EM (m/z): 225 (M⁺; 36%); 197 (M⁺−28; 15%); 182 (M⁺−43; 100%); 154(M⁺−71; 39%);

Elementary Analysis (calculated/experimental):

-   C—53.33%/53.80%;-   H—4.03%/4.50%;-   N—18.66%/18.40%.

e—1-(2,5-dimethoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole (121e)

The derivative 121e was prepared with 98.0% of output, as of thefluoridation reaction to the derivative4-carboxaldehyde-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole (114e) withthe diethylamino sulphur trifluoride, DAST, thus obtaining a white solidwith fusion point at 78.0-79.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 3.84 (s, 3H, 5′ OCH₃); 3.88(s, 3H, 2′ OCH3) 6.97 (t, 1H, CHF₂, J=55.0 Hz); 6.99 (dd, 1H, H4′, J=3.0Hz); 7.04 (d; 1H, H3′, J=3.0 Hz); 7.43 (d, 1H, H6′, J=3.0 Hz); 8.43 (s,1H, H5);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ (ppm)): *55.9 (3H, 3′OCH₃); *56.5(3H, 5′OCH₃); 110.3 (t, CF₂H, J=230.0 Hz); 113.6 (C4′); 116.2 (C3′ andC6′); 124.4 (C5); 121.1 (C6′); 127.3 (C1′); 142.3 (t, C4, J=29.1 Hz)144.7 (C2′); 153.9 (C5′);

¹⁹F RMN (376.0 MHz, CDCl₃/CFCl₃; δ (ppm)): −112.2 (2F,CHF₂);

IV (KBr) cm⁻¹: 3169 (ν C—H); 1027 (ν C—F and C—O);

EM (m/z): 255 (M⁺; 60%); 227 (M⁺−28; 8%); 226 (M⁺−29; 5%); 212 (M⁺−43;100%);

Elementary Analysis (theoretical/experimental):

-   C—51.77%/51.85%;-   H—4.34%/4.58%;-   N—16.46%/16.76%.

f—1-(3-chlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole (121f)

The derivative 121f was prepared with 93.0% of output, as of thereaction of fluoridation to the derivative4-carboxaldehyde-1-(3-chlorophenyl)-1H-1,2,3-triazole (114f) with thediethylamino sulphur trifluoride, DAST, thus obtaining a white solidwith fusion point at 57.6-58.2° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 6.96 (t, 1H, CHF₂, J=54.5Hz); 7.81 (d, 1H, H2′, J=1.5 Hz); 7.66 (dd, 1H, H4′, J=1.2 and 7.5 Hz);*7.65 (m; 1H, H5′, J=2.4 and 8.0 Hz); *7.65 (m, 2H, H6′, J=2.4 and 8.0Hz); 8.24 (s, 1H, H5).

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ (ppm)): 109.8 (t, CF₂H, J=236.5 Hz);120.5 (C5); 118.8 (C2′); 121.1 (C6′); 131.0 (C5′); 135.4 (C4′); 137.2(C1′); 143.6 (t, C4, J=28.1 Hz); 135.8 (C3′);

¹⁹F RMN (376.0 MHz, CDCl₃/CFCl₃; δ (ppm)): −112.6 (2F,CHF₂);

IV (KBr) cm⁻¹: 3146 (ν C—H); 1042 (ν C—F);

EM (m/z): 229 (M;⁺ 60%); 200 (M^(•+)−29; 72%); 182 (M^(•+)−47; 60%); 137(M^(•+)−92; 50%); 111 (M^(•+)−118; 100%); 75 (M^(•+)−154; 70%);

Elementary Analysis (theoretical/experimental):

-   C—47.08%/47.38%;-   H—2.63%/2.89%;-   N—18.30%/17.78%.

g—1-(3,5-dichlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole (121g)

The derivative 121g was prepared with 98.0% of output, as of thereaction of fluoridation to the derivative4-carboxaldehyde-1-(3,4-dichlorophenyl)-1H-1,2,3-triazole (114 g) withthe diethylamino sulphur trifluoride, DAST, thus obtaining a white solidwith fusion point at 83.0-85.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 6.95 (t, 1H, CHF₂, J=54.5Hz); 7.72 (d, 1H, H2′, J=1.5 Hz); 7.49 (dd, 1H, H4′, J=1.0 and 1.5 Hz);7.72 (d, 1H, H6′, J=1.5 Hz); 8.24 (s, 1H, H5).

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ (ppm)); 109.6 (t, CHF₂, J=235.3 Hz);119.2 (C2′ and C6′); 123.0 (C5); 129.5 (C4′); 136.5 (C3′ and C5′); 137.6(C1′); 143.9 (t, C4, J=29.8 Hz).

¹⁹F RMN (376.0 MHz, CDCl₃/CFCl₃; δ (ppm)): −117.6 (2F, CHF₂)

IV (KBr) cm⁻¹: 3160 (ν C—H); 1042 (ν C—F);

EM (m/z): 263 (M⁺; 73%); 235 (M⁺−28; 30%); 234 (M⁺−29; 100%); 216(M⁺−47; 70%);

Elementary Analysis (calculated/experimental):

-   C—40.94%/41.19%;-   H—1.91%/2.32%;-   N—15.91%/14.41%

h—1-(3-cyanophenyl)-4-difluoromethyl-1H-1,2,3-triazole (121h)

The derivative 121h was prepared with 97.0% of output, as of thereaction of fluoridation to the derivative4-carboxaldehyde-1-(3-cyanophenyl)-1H-1,2,3-triazole (114h) with thediethylamino sulphur trifluoride, DAST, thus obtaining a white solidwith fusion point at 119.0-120.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 6.97 (t, 1H, CHF₂, J=54.5Hz); 8.12 (dd, 1H, H2′, J=1.5 and 2.0 Hz); 8.06 (ddd, 1H, H4′, J=1.0;2.0; 3.0 and 8.5 Hz); 7.81 (dd, 1H, H6′, J=1.0 and 7.0 Hz); 7.74 (d, 1H,H5′, J=8.0 Hz); 8.33 (s, 1H, H5);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ (ppm)): 109.6 (t, CHF₂, J=237.3 Hz);114.4 (C3′); 117.1 (CN); 120.0 (C5); 124.0 (C5′); 124.7 (C6′); 131.1(C4′); 132.8 (C2′); 137.0 (C1′); 143.9 (t, C4, J=29.5 Hz);

¹⁹F RMN (376.0 MHz, CDCl₃/CFCl₃; δ (ppm)): −112.9 (2F, CHF₂)

IV (KBr) cm⁻¹: 3156 (ν C—H); 2235 (ν CN); 1042 (ν C—F);

EM (m/z): 220 (M⁺; 24%); 192 (M⁺−28; 20%); 191 (M⁺−29; 63%); 173 (M⁺−47;52%); 128 (M⁺−92; 45%); 102 (M⁺−118; 100%);

Elementary Analysis (calculated/experimental):

-   C—54.55%/55.10%;-   H—2.75%/2.95%;-   N—25.45%/24.70%.

i—1-(4-cyanophenyl)-4-difluoromethyl-1H-1,2,3-triazole (121i)

The derivative 121i was prepared with 98.0% of output, as of thereaction of fluoridation to the derivative4-carboxaldehyde-1-(4-cyanophenyl)-1H-1,2,3-triazole (114i) with thediethylamino sulphur trifluoride, DAST, thus obtaining a white solidwith fusion point at 126.0-128.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 6.97 (t, 1H, CHF₂, J=54.5Hz); 7.89 (dd, 2H, H3′ and H5′, J=2.0 and 7.0 Hz); 7.96 (dd, 1H, H2′ andH6′, J=1.5 and 7.0 Hz); 8.35 (s, 1H, H5);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ (ppm)): 109.7 (t, CHF₂, J=235.0 Hz);114.4 (C3′); 117.1 (CN); 120.0 (C5); 124.0 (C5′); 124.7 (C6′); 131.1(C4′); 132.8 (C2′); 137.0 (C1′); 143.9 (t, C4, J=29.1 Hz);

¹⁹F RMN (376.0 MHz, CDCl₃/CFCl₃; δ (ppm)): −112.9 (2F,CHF₂);

IV (KBr) cm⁻¹: 3139 (ν C—H); 2235 (ν CN); 1040 (ν C—F);

EM (m/z): 220 (M⁺; 42%); 192 (M⁺−28; 42%); 191 (M⁺−29; 100%); 173(M⁺−47; 74%); 128 (M⁺−92; 58%); 102 (M⁺−118; 92%);

Elementary Analysis (calculated/experimental):

-   C—54.55%/55.15%;-   H—2.75%/2.84%;-   N—25.45%/22.68%.

j—1-(4-nitrophenyl)-4-difluoromethyl-1H-1,2,3-triazole (121j)

The derivative (121j) was prepared with 93.0% of output, as of thereaction of fluoridation to the derivative4-carboxaldehyde-1-(4-nitrophenyl)-1H-1,2,3-triazole (114j) with thediethylamino sulphur trifluoride, DAST, thus obtaining an amorphousyellow solid with fusion point at 161.0-163.0° C.

¹H RMN (500.00 MHz; DMSO_(d6)/Me₄Si; δ (ppm)): 6.98 (t, 1H, CF₂H, J=54.5Hz); 8.02 (d, 2H, H2′ and H6′, J=7.5 Hz); 8.47 (d, 2H, H3′ and H5′,J=7.5 Hz); 8.35 (s, 1H, H5);

¹³C RMN (125.0 MHz, DSMO_(d6)/Me₄Si; δ (ppm)): 109, δ (t, CF₂H, J=236.9Hz); 120.5 (C5); 120.9 (C2′ and C6′); 125.6 (C3′ and C5′); 140.5 (C1′);144.2 (C4); 147.7 (C4′).

¹⁹F RMN (376.0 MHz, DMSO_(d6)/CFCl₃; δ (ppm)): −113.0 (2F, CHF₂)

IV (KBr) cm⁻¹: 3142 (ν C—H_(ar)); 1526 (νNO₂); 1341 (νNO₂); 1039 (νC—F);

EM (m/z): 240 (M⁺; 30%); 212 (M⁺−28; 40%); 211 (M⁺−29; 32%); 193 (M⁺−47;18%); 166 (M⁺−74; 28%); 76 (M⁺−164, 100%);

Elementary Analysis (theoretical/experimental):

-   -   C—45.01%/44.76%;    -   H—2.53%/3.01%;    -   N—23.33%/22.53%.

l—1-(2-methoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole (121l)

The derivative 121l was prepared with 96.0% of output, as of thereaction of fluoridation to the derivative4-carboxaldehyde-1-(2-methoxyphenyl)-1H-1,2,3-triazole (114l) with thediethylamino sulphur trifluoride, DAST, thus obtaining a white solidwith fusion point at 65.0-66.0° C.

¹H RMN (400.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 3.92 (d, ¹H, OCH₃, J=4.0);6.97 (t, CHF₂, J=72.0 Hz); 7.12 (d, 2H, H4′ eH5′, J=8.0 Hz); 7.46 (ddd,1H, H3′, J=4.0 and 8.0 Hz); 7.79 (d, 1H, H6′, J=8.0 Hz);

¹³C RMN (100.0 MHz; CDCl₃/Me₄Si; δ (ppm)): 56.0 (3H, OCH₃); 110.3 (t,CHF₂, J=235.0 Hz); 112.3 (C3′); 124.4 (C5); 121.3 (C5′); 125.4 (C6′);130.6 (C4′); 151.0 (C2′); 137.0 (C1′); 142.2 (t, C4);

¹⁹F RMN (376.0 MHz; CDCl₃/CFCl₃; δ (ppm)): −112.1 (2F,CHF₂);

IV (KBr) cm⁻¹: 3160 (ν C—H); 1035 (ν C—F);

EM (m/z): 225 (M⁺; 90%); 196 (M⁺−29; 18%); 182 (M⁺−43; 80%); 163 (M⁺−62;20%); 154 (M⁺−71; 48%); 132 (M⁺−93; 58%); 92 (M⁺−133; 72%); 77 (M⁺−148;98%); 51 (M⁺−174; 100%);

Elementary Analysis (calculated/experimental):

-   C—53.33%/53.71%;-   H—4.03%/4.52%;-   N—18.66%/18.70%.

m—1-(3,4-dimethoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole (121m)

The derivative 121m was prepared with 95.0% of output of the reaction offluoridation of the derivative4-carboxaldehyde-1-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole (114m) withthe diethylamino sulphur trifluoride, DAST, thus obtaining a white solidwith fusion point at 62.5-63.5° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm)): 3.96 (s, 6H, 3′OCH₃ and4′OCH₃); 6.95 (t, 1H, CHF₂, J=54.3 Hz); 6.97 (d, 1H, H5′, J=9.0 Hz);7.33 (d, 1H, H2′, J=2.5 Hz); 7.18 (dd, 1H, H6′, J=2.5 and 8.5 Hz); 8.16(s1, 1H, H5).

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ (ppm)): 56.2 (6H, 3′OCH₃ and 5′OCH₃);110.0 (t, CF₂H, J=234.5 Hz); 120.7 (C5); 111.1 (C2′); 112.8 (C6′); 105.1(C5′); 129.9 (C1′); 143.2 (t, C4, J=29.0 Hz); 149.8 (C3′ and C4′).

¹⁹F RMN (376.0 MHz, CDCl₃/CFCl₃; δ (ppm)): −112.2 (2F,CHF₂)

IV (KBr) cm⁻¹: 3160 (ν C—H); 1035 (ν C—F);

EM (m/z): 255 (M⁺; 60%); 277 (M⁺−28; 8%); 226 (M⁺−29; 5%); 208 (M⁺−47;6%);

Elementary Analysis (theoretical/experimental):

-   C—51.77%/51.96%;-   H—4.34%/4.96%;-   N—16.46%/16.10%.    C—General Method of obtainment of type III 1,2,3-triazole    derivatives

Below you will find a detailed description of the obtainment of type IIIcompounds that were confirmed by analytical methods represented by FIG.3.

In a rounded bottom 50 mL balloon containing 1.1 mol ofdiazomalonaldehyde dissolved in a 2:1 solution of methanol/water, 1.0mol of the desired derivative aniline and 0.1 mL of acetic acid wereadded. The reaction was maintained under disturbance, at roomtemperature and after 24 h the solvent was evaporated and the productinsulated. This methodology was used to obtain the below mentionedcompounds:

1.(E)-4-chloride-N-((1-(4-chlorophenyl)-1H-1,2,3-triazole-4-il)methylene)benzenamine(119)

The derivative (119) was prepared with 73.0% of output, as of thereaction of diazomalonaldehyde with p-chlorideaniline, in an acidenvironment, thus obtaining an amorphous yellow solid with fusion pointat 208° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm))*: 7.09 (d, 2H, H2″ and H6″,J=9 Hz); 7.19 (d, 2H, H3″ and H5″, J=9 Hz); 7.54 (d, 2H, H2′ and H6′,J=9 Hz); 7.74 (d, 2H, H3′ and H5′, J=9 Hz); 8.57 (s, 1H, HCN); 8.71 (s,1H, H5);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 121.0 (C5); 121.7 (C2″ andC6″); 122.2 (C3″ and C5″); 129.4 (C3″ and C5″); 130.1 (C3′ and C5′);132.4 (C1′); 135.2 (C4″); 135.2 (C4′); 116.2 (C4); 147.1 (C1″); 151.8(CHN);

IV (KBr) cm⁻¹: 3111 (ν C—H_(ar)); 1635 (ν C—H_(imina));

EM (m/z):): 316 (M⁺; 27%); 287 (M⁺−29; 100%); 218 (M⁺−98; 50%); 111(M⁺−205; 95%).

2.(E)-4-bromo-N-((1-(4-bromophenyl)-1H-1,2,3-triazole-4-il)methylene)benzenamine(120)

The derivative (120) was prepared with 80.0% of output, as of thereaction of diazomalonaldehyde with the p-bromoaniline, in an acidenvironment, thus obtaining an amorphous yellow solid with fusion pointat 208-210.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si; δ (ppm))*: 7.20 (d, 2H, H2″ and H6″,J=9.0 and 2.0 Hz); 7.38 (dd, 2H, H3″ and H5″, J=9.0 and 2.0 Hz); 7.55(dd, 2H, H2′ and H6′, J=9.0 and 2.0 Hz); 7.75 (dd, 2H, H3′ and H5′,J=9.0 and 2.0 Hz); 8.58 (s, 1H, HCN); 8.71 (s, 1H, H5);

¹³C RMN (125.0 MHz, CDCl₃/Me₄Si; δ(ppm)): 121.0 (C5); 121.7 (C2″ andC6″); 122.2 (C2′ and C6′); 129.4 (C3″ and C5″); 130.1 (C3′ and C5′);132.4 (C1′); 135.0 (C4″); 135.2 (C4′); 147.4 (C4); 149.3 (C1″); 151.8(CHN);

IV (KBr) cm⁻¹: 3109 (ν C—H_(ar)); 1635 (ν C—H_(imina));

EM (m/z): 406 (M⁺; 5%); 377 (M⁺−29; 12%); 218 (M⁺−188; 100).

EXAMPLE 3

A—Pharmacological Analysis of Type I (Formula XII) and II (Formula XIII)Imidazole Derivatives

A.1—Antimicrobial Activity

The imidazole derivatives with general formula XII and XIII weresubmitted to a primary biological evaluation, in vitro, regarding theinhibitory activity of Mycobacterium tuberculosis H37Rv (ATCC-27294).

The assessment of the minimum inhibitory (MIC) of the substances, thatis, the smallest concentration of the compound where the bacterialgrowth is not observed, was made using the colorimetric method known asMABA (Microplate Alamar Blue Assay). This method consists in an essayperformed by the micro dilution in plates, using, as cell growthindicator, the Alamar Blue® indicator pigment, which is afluorescent/colorimetric indicator with redox property. The oxidizedform is blue (non-fluorescent) and indicates the absence of bacterialgrowth. The reduced form presents a pink color (fluorescent), indicatesthe proliferation of bacteria.

To perform the essay, sterile micro plates with 96 wells were used in away that each well presented a total of 200 μL of a mixture composed bythe adequate culture mean, of the compound to be tested and of thebacterial suspension. The comparison pattern used was rifampicin, whichpresents a MIC equal to 1.0 μg/mL.

After 5 incubation days, 15 μL of Alamar Blue® was added to each welland microplates were incubated for more than 24 hours at 37° C. At theend of this period of time, the change of color in each well wasobserved, and MIC was defined as the smallest concentration of thecompound that delimitates the change from blue to pink. Thus, theantimicrobial activity essay of compounds of the type I (Formula XII)and II (Formula XIII) imidazole derivatives and they were able toinhibit the bacterial growth in low concentrations presenting MIC withvalues 3.0-1.2 μg/mL.

As an example, in table 4, there is a list of the values assessed forMIC, μg/mL, of 146a, 140b, 146c and 146e derivatives.

TABLE 4 Antimicrobial evaluation of the type I (Formula XII) imidazolederivatives

 

MIC 3.0 μg/mL 1.2 μg/mL 3.0 μg/mL 3.0 μg/mL

Table 5 shows examples of MIC values assessed for type II (Formula XIII)imidazole derivatives.

TABLE 5 Antimicrobial evaluation of the type II (Formula XIII) imidazolederivatives

 

MIC 3.0 μg/mL 3.0 μg/mL 3.0 μg/mL 3.0 μg/mLA.2—Leishmanicide Activity

The evaluation of the leishmanicide activity of type I (Formula XII) andII (Formula XIII) imidazole derivatives was performed through in vitroessays against promastigote forms of Leishmania amazonensis, and afterthe incubation with compounds, live parasites are counted byfluorescence, thus obtaining as a result the inhibition percentage ofthe evaluated compounds.

Essays were performed in triplicate using pentamidine as a positivepattern with a 160 μg/mL concentration, determining which compoundsevaluated inhibited the parasite in lower concentrations and thepercentage higher than the pattern. Table 6 lists the results obtainedin the leishmanicide evaluation of derivatives 140a 148a 146a, 149a.

TABLE 6 Evaluation of the leishmanicide activity of type I (Formula XII)and II (Formula XIII) imidazole derivatives Compounds                      Conc. μ/mL          

320 160 53% 80 No inhibition 20 No inhibition 10 No inhibition 79% 5 Noinhibition No inhibition Compounds                       Conc. μ/mL

320 160 93% 80 75% No 20 inhibition No No inhibition inhibition 10 90%No No inhibition inhibition 5 No No No inhibition inhibition inhibition

EXAMPLE 4

Below there is a detailed description of the obtainment of the imidazolecompounds substituted twice and substituted that were confirmed byanalytical methods represented in FIG. 4.

A—General Method of Obtainment of Type I (Formula XII)—140a-e and 146a-eImidazole Derivatives

In a 25 mL volumetric flask 5.0 mmol of the desired derivative 134a-ewas weighed and 5 mL of dry piridine was added. The solution was shakenuntil complete dissolution of the starting material. Then 15 mmol acidchloride was slowly added. The reaction mixture was shaken, at roomtemperature, for 17 hours. After this period, 15.0 mmol sodiumbicarbonate was added. The suspension was shaken until stopping theeffervescency and the solvent was evaporated. The residue obtained wassuspended in 40.0 mL of dichloromethane, washed with water (3×20 mL) andwith a saturated NaHCO₃ (3×15 mL) solution. The organic stage was driedwith filtered sodium sulfate and the solvent evaporated. The productobtained was purified by recrystallization with 1:1 ethylacetate:hexane.

The following products were obtained using this methodology:

A.1—As of the Chloride of 4-Fluorobenzoic (144)

1. Ester ethyl5-[(bis(4-fluorobenzoic)amino]-1-(4-methylphe-nyl)-1H-imidazole-4-carboxylate(140a)

The derivative 140a was obtained with 81% of output in the form ofcolorless crystals with fusion point at 203-205° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.36 (t, 3H, CH ₃, J=7.2 Hz);2.38 (s, 3H, CH ₃); 4.37 (q, 2H, CH ₂ J=7.2 Hz); 7.64 (s, 1H, H₂); 7.03(d, 2H, H_(3′) and H_(5′), J=8.4 Hz); 7.20 (d, 2H, H_(2′) and H_(6′),J=8.0 Hz); 6.95 (d, 4H, H_(3a,3b) and H_(5a, 5b), J=8.4 and 2.0 Hz);7.56 (d, 4H, H_(2a,2b) and H_(6a,6b), J=8.4 and 2.0 Hz);

¹³C RMN (125.0 MHz) (DMSO_(d6)/Me₄Si) δ (ppm): 14.4 (CH₂ CH₃); 58.5(CH₂CH₃); 115.7 (C_(3ab-5ab); ²J_(CF)=22.3 Hz); 125.8 (C_(3′) andC_(5′)); 126.6 (C₄); 127.9 (C_(4′)); 129.8 (C_(1ab)); 130.4 (C_(2′) andC_(6′)); 131.8 (C_(2ab-6ab); ³J_(CF)=9.4 Hz); 132.9 (C₂); 136.2(C_(1′)); 140.6 (C₅); 161.5 (NC═O); 165.4 (C_(4ab-) ¹J_(CF)=253.8 Hz);170.7 (OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 1705 (C═O); 1250 (C—F; C—O);

EM (m/z): 489.47 (M^(•+)) 123 (M^(•+)−366.47; 100%).

2. Ester ethyl5-[(bis(4-fluorobenzoic)amino]-1-(4-cyanophe-nyl)-1H-imidazole-4-carboxylate(140b)

The derivative 140b was obtained with 87% of output in the form ofcolorless crystals with fusion point at 206-208° C.

¹H RMN (400.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.36 (t, 3H, CH ₃, J=8.0 Hz);4.38 (q, 2H, CH ₂ J=8.0 Hz); 7.63 (s, 1H, H₂); 7.34 (d, 2H, H_(2′) andH_(6′), J=8.0 Hz); 7.74 (d, 2H, H_(3′) and H_(5′), J=8.0 Hz); 6.99 (d,4H, H_(3a,3b) and H_(5a, 5b), J=8.5 Hz); 7.60 (dq, 4H, H_(2a,2b) andH_(6a,6b), J=8.6; 3.4 and 2.0 Hz);

¹³C RMN (100.0 MHz) (CDCl₃/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 61.4(CH₂CH₃); 117.1 (CN); 114.2 (C_(4′)); 115.0 (C_(3a-5ab); ²J_(CF)=23.0Hz); 126.5 (C_(2′) and C_(6′)); 127.8 (C_(4′)); 129.3 (C_(1ab)); 131.9(C_(2ab-6ab); ³J_(CF)=8.0 Hz); 132.6 (C₂); 133.8 (C_(3′) and C_(5′));135.7 (C_(1′)); 136.6 (C₅); 165.4 (C_(4ab-) ¹J_(CF)=256.0 Hz); 170.0(OC═O); 161.6 (NC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 2230 (CN); 1695 (C═O); 1250 (CF; CO)

EM (m/z): 500.45 (M^(•+)) 123 (M^(•+)−377.45; 100%).

3. Ester ethyl5-[(bis(4-fluorobenzoic)amino]-1-(4-chlorophe-nyl)-1H-imidazole-4-carboxylate(140c)

The derivative 140c was obtained with 87% of output in the form ofcolorless crystals with fusion point at 225-227° C.

¹H RMN (400.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.38 (t, 3H CH ₃, J=7.2 Hz);4.38 (q, 2H, CH ₂ J=7.2 Hz); 7.59 (s, 1H, H₂); 7.40 (dd, 2H, H_(2′) andH_(6′), J=8.0 and 2.8 Hz); 7.11 (d, 2H, H_(3′) and H_(5′), J=8.4 and 2.8Hz); 6.97 (dq, 4H, H_(3a,3b) and H_(5a, 5b), J=8.8, 2.8 and 2.0 Hz);7.59 (dq, 4H, H_(2a,2b) and H_(6a,6b), J=8.8; 3.6 and 2.0 Hz);

¹³C RMN (100.0 MHz) (CDCl₃/Me₄Si) δ (ppm): 140.3 (CH₂ CH₃); 61.2(CH₂CH₃); 115.8 (C_(3ab-5ab); ²J_(CF)=22.3 Hz); 127.3 (C_(2′) andC_(6′)); 129.6 (C_(1ab)); 130.1 (C_(3′) and C_(5′)); 131.5 (C₂); 131.8(C_(2ab-6ab); ³J_(CF)=8.9 Hz); 131.9 (C₄); 131.9 (C₅); 136.1 (C_(4′));136.1 (C_(1′)); 161.7 (NC═O); 165.3 (C_(4ab); ¹J_(CF)=254.5 Hz); 170.7(OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 1700 (C═O); 1242 (CF_(r); CO);

EM (m/z): 509.89 (M^(•+)) 123 (M^(•+)−386.89; 100%).

4. Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(3,5-dichlorophenyl)-1H-imidazole-4-carboxylate (140d)

The derivative 140d was obtained with 78% of output in the form ofcolorless crystals with fusion point at 140-142.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.36 (t, 3H CH ₃, J=7.0 Hz);4.37 (q, 2H, CH ₂ J=7.0 Hz); 7.61 (s, 1H, H₂); 7.26 (d, 2H, H_(2′) andH_(6′), J=1.5 Hz); 7.61 (t, 1H, H_(4′), J=1.5 Hz); 6.99 (t, 4H,H_(3a,3b) and H_(5a, 5b), J=8.5 Hz); 7.63 (ddd, 4H, H_(2a,2b) andH_(6a,6b), J=7.5; 3.5 and 2.0 Hz);

¹³C RMN (125.0 MHz) (CDCl₃/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 61.3(CH₂CH₃); 115.8 (C_(3ab-5ab); ²J_(CF)=21.8 Hz); 124.5 (C_(2′) andC_(6′)); 127.9 (C_(4′)); 129.6 (C_(1ab)); 130.3 (C_(4′)); 131.9 (C₂);131.9 C_(2ab-6ab); ³J_(CF)=7.5 Hz); 132.6 (C_(1′)); 135.7 (C_(3′) andC_(5′)); 136.3 (C₅); 161.6 (NC═O); 165.3 (C_(4ab); ¹J_(CF)=254.7 Hz);170.7 (OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 1708 (C═O); 1236 (CF; C—O)

EM (m/z): 544.33 (M^(•+)) 123 (M^(•+)−421.33; 100%);

5. Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(2,6-di-fluorophenyl)-1H-imidazole-4-carboxylate (140e)

The derivative 140d was obtained with 77% of output in the form ofcolorless crystals with fusion point at 178-181.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.35 (t, 3H CH ₃, J=7.0 Hz);4.36 (q, 2H, CH ₂ J=7.0 Hz); 7.60 (m, 5H, H₂, H_(2a,2b) and H_(6a,6b),J=8.5; 5.0 and 3.5 Hz); 7.26 (d, 2H, H_(3′) and H_(3′), J=1.5 Hz); 7.61(t, 1H, H_(4′), J=1.5 Hz); 6.98 (m, 4H, H_(3a,3b) and H_(5a, 5b), J=8.5Hz).

¹³C RMN (125.0 MHz) (CDCl₃/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 61.2(CH₂CH₃); 112.6 (C_(3′) and C_(5′); ⁴J_(CF)=3.6 Hz); 111.0 (C_(1′));115.8 (C_(3ab-5ab); ²J_(CF)=22.1 Hz); 127.2 (C₄); 129.7 (C_(1ab);⁴J_(CF=)3.0 Hz); 131.6 (C_(2ab-6ab); ³J_(CF)=9.2 Hz); 131.6 (C₂); 132.3(C_(4′); ³J_(CF)=9.3 Hz); 137.2 (C₅); 157.8 (C_(2′) and C_(6′);¹J_(CF)=256.0 Hz); 161.6 (NC═O); 165.2 (C_(4ab); ¹J_(CF)=254.0 Hz);169.5 (OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 1726; 1694 (C═O); 1236 (CF; CO)

EM (m/z): 511.12 (M^(•+)); 123 (M^(•+)−388.12; 100%)

A.2—As of the chloride of 2-fluorobenzoic (145)

1. Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate (146a)

The derivative 146a was obtained with 83% of output in the form oftransparent crystals with fusion point at 176.5° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.35 (t, 3H, CH ₃, J=10.0 Hz);3.83 (s, 3H, CH ₃); 4.38 (q, 2H, CH ₂ J=10.0 Hz); 6.86 (t, 2H,H_(3a,3b); J=5.0 Hz); 6.95 (d, 2H, H_(3′) and H_(5′), J=10.0 Hz); 7.18(d, 2H, H_(2′) and H_(6′), J=10.0 Hz); 7.24 (t, 2H, H_(5a,2b); J=5.0Hz); 7.33 (d, 2H, H_(4a,b); J=5.0 Hz); 7.50 (s1, 2H, H_(6a,b)); 7.61 (s,1H, H₂);

¹³C RMN (125.0 MHz) (DMSO_(d6)/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 60.9(CH₂CH₃); 21.1 (CH₃); 114.8 (C_(2′) and C_(6′)); 116.1 (C_(3ab);²J_(CF)=21.5 Hz); 122.4 (C_(1ab); ²J_(CF)=11.2 Hz); 124.0 (C_(5ab);⁴J_(CF)=2.5 Hz); 127.3 (C_(3′) and C_(5′)); 128.0 (C₄); 128.6 (C_(4′));130.6 (C_(6ab)); 131.2 (C₅); 133.2 (C_(1′)); 134.1 (C_(4ab) ³J_(CF)=8.7Hz); 136.7 (C₂); 159.5 (C_(2ab); ¹J_(CF)=255.0 Hz); 160.6 (NC═O); 167.1(OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 1692 (C═O); 1257 (CF; C—O);

EM (m/z): 489.47 (M^(•+)) 123 (M^(•+)−366.47; 100%);

2. Ester ethyl5-[(bis(2-fluorobenzoic)amino]-1-(4-chloridephe-nyl)-1H-imidazole-4-carboxylate(146c)

The derivative 146c was obtained with 80% of output in the form oftransparent crystals with fusion point at 199-200.0° C.

¹H RMN (400.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.35 (t, 3H, CH ₃, J=7.2 Hz);4.38 (q, 2H, CH ₂ J=7.2 Hz); 6.85 (t, 2H, H_(3a,3b); J=9.6 Hz); 7.06 (t,2H, H_(5a, b); J=7.6 Hz); 7.24 (d, 2H, H_(2′) and H_(6′), J=8.4 Hz);7.33 (dq, 2H, H_(4a, b); J=7.2 and 4.0 Hz); 7.45 (d, 2H, H_(3′) andH_(5′), J=8.4 Hz); 7.51 (t, 2H, H_(6ab), J=7.2 and 6.4 Hz); 7.74 (s, 1H,H₂);

¹³C RMN (100.0 MHz) (DMSO_(d6)/Me₄Si) δ (ppm): 14.2 (CH₂ CH₃); 61.2(CH₂CH₃); 127.3 (C_(2′) and C_(6′)); 116.1 (C_(3ab); ²J_(CF)=21.7 Hz);122.2 (C_(1ab); ²J=12.1 Hz); 124.2 (C_(5ab)); 128.1 (C₄); 128.6(C_(4′)); 130.8 (C_(3′) and C_(5′)); 130.1 (C_(6ab)); 131.2 (C₅); 131.7(C_(1′)); 134.4 (C_(4ab) ³J_(CF)=8.4 Hz); 136.3 (C₂); 159.5 (C_(2ab);¹J_(CF)=243.1 Hz); 160.7 (NC═O); 166.9 (OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 1719 (C═O); 1233 (CF; CO);

EM (m/z): 509.89 (M^(•+)) 123 (M^(•+)−386.89; 100%);

3. Ester ethyl5-[(bis(2-fluorobenzoic)amino]-1-(3,5-dichloride-phenyl)-1H-imidazole-4-carboxylate(146d)

The derivative 146d was obtained with 83% of output in the form oftransparent crystals with fusion point at 140-142.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.34 (t, 3H, CH ₃, J=7.2 Hz);4.38 (q, 2H, CH ₂ J=7.2 Hz); 6.87 (t, 2H, H_(3a,3b); J=9.6 Hz); 7.09 (t,2H, H_(5a, b); J=7.6 Hz); 7.24 (d, 2H, H_(2′) and H_(6′), J=1.6 Hz);7.35 (dq, 2H, H_(4a, b); J=7.2 and 4.8 Hz); 7.45 (d, 1H, H_(4′); J=1.6Hz); 7.58 (t, 2H, H_(6ab), J=7.5 and 6.5 Hz); 7.66 (s, 1H, H₂);

¹³C RMN (125.0 MHz) (DMSO_(d6)/Me₄Si) δ (ppm): 14.2 (CH₂ CH₃); 61.1(CH₂CH₃); 124.4 (C_(2′) and C_(6′)); 116.0 (C_(3ab); ² J_(CF)=22.3 Hz);122.1 (C_(1ab); ²J_(CF)=11.6 Hz); 124.2 (C_(5ab)); 128.9 (C4); 130.1(C_(4′)); 136.0 (C_(3′) and C_(5′)); 130.9 (C_(6ab)); 131.0 (C5); 131.7(C_(1′)); 134.9 (C_(4ab) ³J_(CF)=10.0 Hz); 136.3 (C₂); 159.7 (C_(2ab);¹J_(CF)=260.8 Hz); 160.6 (NC═O); 166.8 (OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 1705 (C═O); 1239 (CF; CO);

EM (m/z): 544.33 (M^(•+)) 123 (M^(•+)−421.45; 100%);

4. Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(2,6-difluoro-phenyl)-1H-imidazole-4-carboxylate (146e)

The derivative 146e was obtained with 80% of output in the form oftransparent crystals with fusion point at 178-181.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.36 (t, 3H CH ₃, J=7.0 Hz);4.40 (q, 2H, CH ₂ J=7.0 Hz); 7.06 (t, 4H, H_(3′) and H_(5′), J=8.0 Hz);7.06 (t, 4H, H_(5ab); J=8.0 Hz); 7.34 (dq, 2H, H_(4ab); J=12.0, 5.5 and1.5 Hz); 7.46 (dq, 1H, H_(4′), J=6.0 and 2.5 Hz); 7.59 (d, 2H, H_(6ab);J=6.5 Hz); 7.61 (s, 1H, H₂); 7.85 (t, 2H, H_(3ab); J=10.0 Hz);

¹³C RMN (125.0 MHz) (CDCl₃/Me₄Si) δ (ppm): 14.2 (CH₂ CH₃); 61.1(CH₂CH₃); 111.2 (C_(1′); ²J_(CF)=15.0 Hz); 115.8 (C_(3ab); ² J_(CF)=22.1Hz); 122.6 (C_(3′) and C_(5′); ³J_(CF)=19.5 Hz); 122.3 (C_(1ab);³J_(CF)=11.8 Hz); 124.2 (C_(5ab)); 128.6 (C₄); 130.7 (C₅); 130.7(C_(6ab)); 132.3 (C_(4′); ³J_(CF)=9.9 Hz); 134.9 (C_(4ab); ³J_(CF)=10.0Hz); 137.5 (C₂); 157.8 (C_(2ab); ¹J_(CF)=255.3 Hz); 159.5 (C_(2′) andC_(6′); ¹J_(CF)=255.0 Hz); 160.6 (NC═O); 166.8 (OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 1705 (C═O); 1253 (C—F; C—O);

EM (m/z): 511.12 (M^(•+)); 123 (M^(•+)−388.12; 100%).

B—General Method of Obtainment of Type II (Formula XIII) 148a-e 149a-eImidazole Derivatives

In a 50 mL balloon 5 mmol of the desired twice substituted derivative,10 mL of dioxane and 2 mL of 2-propanol were added. The solution wasshaken during some minutes and 5 mmol of 60% hidrazine hydrate wereadded, drip by drip, during some minutes. The reaction mixture wasreflowed for 1 h and 30 min and observing the consume of the startingmaterial, by c.c.f, using ethyl:hexane 7:3 acetate. The solvent wasevaporated and the residue obtained by column chromatography in silicagel using ethyl:hexane 7:3 acetate as eluant.

The following products were obtained using this methodology:

1. Ester ethyl5-[(4-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate(148a)

The derivative 148a was obtained with 74% of output in the form ofcrystals shaped as colorless needles with fusion point at 183-185.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.34 (t, 3H, CH ₃, J=7.0 Hz);2.36 (s, 3H, CH ₃); 4.34 (q, 2H, CH ₂ J=7.0 Hz); 7.09 (t, 2H, H_(3a) andH_(5a); J=8.5 Hz); 7.23 (d, 2H, H_(3′) and H_(5′), J=8.5 Hz); 7.24 (dq,2H, H_(2a) and H_(6a); J=8.5; 5.0 and 3.5 Hz); 7.28 (d, 2H, H_(2′) andH_(6′), J=8.5 Hz); 7.59 (s, 1H, H₂); 9.15 (s, H, NH);

¹³C RMN (125.0 MHz) (DMSO_(d6)/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 60.9(CH₂CH₃); 21.1 (CH₃); 115.7 (C_(3ab-5ab); ²J_(CF)=22.3 Hz); 122.7 (C₄);123.8 (C_(2′) and C_(6′)); 128.9 (C_(1ab); ⁴J_(CF)=3.0 Hz); 130.2(C_(3′) and C_(5′)); 130.2 (C_(2ab-6ab), ³J_(CF)=8.8 Hz); 133.3 (C₅);133.8 (C_(1′)); 135.5 (C₂); 138.9 (C_(4′)); 163.7 (NC═O); 164.8 (OC═O);165.4 (C_(4ab-) ¹J_(CF)=252.5 Hz);

IV (tablet of KBr (1%)) ν (cm⁻¹): 3187 (NH); 1711, 1686 (C═O); 1250(C—F; C—O)

EM (m/z): 367.37 (M^(•+)) 123 (M^(•+)−244.37; 100%)

2. Ester 1-(4-cyanophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate de ethyl (148b)

The derivative 148b was obtained with 73% of output in the form ofcolorless crystals with fusion point at 223-224.0° C.

¹H RMN (400.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.40 (t, 3H, CH ₃, J=7.0 Hz);4.40 (q, 2H, CH ₂ J=7.0 Hz); 7.27 (s, 1H, H₂); 7.14 (t, 2H, H_(3a)eH_(5a) J=8.5 Hz); 7.50 (d, 2H, H_(2′) and H_(6′), J=8.5 Hz); 7.78 (d,2H, H_(3′) and H_(5′), J=8.5 Hz); 7.88 (dq, 2H, H_(2a) and H_(6a);J=8.6; 5.1 and 3.4 Hz); 9.51 (s, H, NH);

¹³C RMN (100.0 MHz) (CDCl₃/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 61.4(CH₂CH₃); 112.8 (C_(4′)); 115.8 (CN); 116.1 (C_(3ab-5ab); ²J_(CF)=22.0Hz); 122.0 (C₄); 124.4 (C_(2′) and C_(6′)); 129.8 (C_(1ab); ⁴J_(CF)=3.2Hz); 130.2 (C_(2ab-6ab); ³J_(CF)=9.1 Hz); 133.8 (C_(3′) and C_(5′));134.1 (C₅); 134.6 (C₂); 139.6 (C_(1′)); 163.5 (NC═O); 164.6 (OC═O);165.5 (C_(4ab); ¹J_(CF)=287.5 Hz);

IV (tablet of KBr (1%)) ν (cm⁻¹): 3246 (NH); 2227 (CN); 1716 and 1661(C═O);

EM (m/z): 378.36 (M^(•+)) 123 (M^(•+)−255.45; 100%);

3. Ester ethyl1-(4-chlorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate(148c)

The derivative 148c was obtained with 75% of output in the form ofcrystals with fusion point at 174-177° C.

¹H RMN (400.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.38 (t, 3H CH ₃, J=7.2 Hz);4.38 (q, 2H, CH ₂ J=7.2 Hz); 7.61 (s, 1H, H₂); 7.37 (d, 2H, H_(2′) andH_(6′), J=8.8 Hz); 7.43 (d, 2H, H_(3′) and H_(5′), J=8.4 Hz); 7.13 (t,2H, H_(3a) and H_(5a) J=8.4 Hz); 7.87 (dq, 2H, H_(2a) and H_(6a); J=8.4;5.1 and 3.4 Hz); 9.21 (s, 1H, NH);

¹³C RMN (100.0 MHz) (CDCl₃/Me₄Si) δ (ppm): 14.2 (CH₂ CH₃); 61.1(CH₂CH₃); 116.8 (C_(3a-5a); ²J_(CF)=22.0 Hz); 125.3 (C_(2′) and C_(6′));128.6 (C_(1ab)); 129.9 (C_(3′) and C_(5′)); 135.1 (C₂); 130.2(C_(2a-6a); ³J_(CF)=9.0 Hz); 122.2 (C₄); 134.9 (C₅); 134.9 (C_(4′));134.3 (C_(1′)); 164.5 (NC═O); 165.5 (C_(4a); ¹J_(CF)=253.0 Hz); 164.5(OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 3290 (NH); 1700 and 1664 (C═O);

EM (m/z): 387.79 (M^(•+)) 123 (M^(•+)−264.89; 100%);

4. Ester ethyl 1-(3,5-dichlorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate(148d)

The derivative 148d was obtained with 77% of output in the form ofcrystals with fusion point at 141-142.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.37 (t, 3H CH ₃, J=7.0 Hz);4.38 (q, 2H, CH ₂ J=7.0 Hz); 7.15 (t, 2H, H_(3a) and H_(5a) J=8.5 Hz);7.36 (d, 2H, H_(2′) and H_(6′), J=2.0 Hz); 7.40 (d, 1H, H_(4′), J=2.0Hz); 7.60 (s, 1H, H₂); 7.90 (ddd, 2H, H_(2a) and H_(6a), J=8.5; 5.0 and3.5 Hz); 9.39 (s, 1H, NH);

¹³C RMN (125.0 MHz) (CDCl₃/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 61.2(CH₂CH₃); 116.1 (C_(3a-5a), ²J_(CF)=220.0 Hz); 122.3 (C₄); 122.5 (C_(2′)and C_(6′)); 128.5 (C_(1ab); ⁴J_(CF)=2.8 Hz); 129.1 (C_(4′)); 130.2(C_(2a-6a); ³J_(CF)=9.25 Hz); 134.0 (C₅); 134.8 (C_(3′) and C_(5′));136.0 (C₂); 137.6 (C_(1′)); 163.6 (NC═O); 164.7 (OC═O); 165.6 (C_(4ab);¹J_(CF)=253.1 Hz);

IV (tablet of KBr (1%)) ν (cm⁻¹): 3290 (NH); 1708 and 1678 (C═O);

EM (m/z): 422.24 (M^(•+)) 123 (M^(•+)−299.24; 100%).

5. Ester ethyl 1-(2,6-difluorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate (148e)

The derivative 148e was obtained with 77% of output in the form ofcrystals with fusion point at 179.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.41 (t, 3H CH ₃, J=7.0 Hz);4.41 (q, 2H, CH ₂ J=7.0 Hz); 7.84 (dq; 2H; H_(2a) and H_(6a); J=8.5; 5.1and 3.4 Hz); 7.09 (m, 4H, H_(3′) and H_(5′). J=8.5 and 3.0 Hz); 7.40 (m,1H, H_(4′), J=8.5, 6.0 and 2.5 Hz); 7.09 (m, 4H, H_(3a) and H_(5a);J=8.5 Hz); 7.54 (s, 1H, H₂); 9.48 (s, 1H, NH);

¹³C RMN (125.0 MHz) (CDCl₃/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 61.2(CH₂CH₃); 112.5 (C_(3′) and C_(5′); ²J_(CF)=22.0 Hz; ⁴J_(CF)=3.6 Hz);114.2 (C_(1′); ²J_(CF)=16.0 Hz); 116.0 (C_(3a-5a); ²J_(CF)=22.1 Hz);127.2 (C₄); 129.7 (C_(1a); ⁴J_(CF)=2.8 Hz); 130.2 (C_(2a-6a);³J_(CF)=9.25 Hz); 130.8 (C_(4′); ³J_(CF)=9.6 Hz); 131.6 (C₂); 137.2(C₅); 157.2 (C_(2′) and C_(6′); ¹J_(CF)=250.0 Hz and ³J_(CF)=3.0 Hz);163.9 (NC═O); 164.0 (OC═O); 165.5 (C_(4a); ¹J_(CF)=252.6 Hz);

IV (tablet of KBr (1%)) ν (cm⁻¹): 3297 (NH); 1718 (C═O);

EM (m/z): 389.33 (M^(•+)); 123 (M^(•+)−266.33; 100%);

6. Ester ethyl5-[(2-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate(149a)

The derivative 149a was obtained with 76% of output in the form ofcrystals with fusion point at 166.0-167.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.37 (t, 3H, CH ₃, J=7.0 Hz);2.37 (s, 3H, CH ₃); 4.39 (q, 2H, CH ₂ J=7.0 Hz); 7.24 (m, 2H,H_(3a and 5a); J=8.4 and 4.9 Hz); 7.25 (d, 2H, H_(3′) and H_(5′), J=8.2Hz); 7.30 (d, 2H, H_(2′) and H_(6′), J=8.2 Hz); 7.55 (d, 1H, H_(4a);J=7.4 and 5.8 Hz); 7.91 (t, 1H, H_(6a); J=7.5 Hz); 7.65 (s, 1H, H₂);9.21 (d, 1H, NH, J=13.5 Hz);

¹³C RMN (125.0 MHz) (DMSO_(d6)/Me₄Si) δ (ppm): 14.3(CH₂ CH₃); 60.9(CH₂CH₃); 21.1 (CH₃); 116.5 (C_(3a); ²J_(CF)=3.7 Hz); 119.1 (C_(1a);²J_(CF)=11.2 Hz); 123.2 (C₄); 123.8 (C_(2′) and C_(6′)); 124.9 (C_(5a);⁴J_(CF)=3.1 Hz); 130.2 (C_(3′) and C_(5′)); 132.2 (C_(6a)); 132.5 (C₅);133.2 (C_(1′)); 134.5 (C_(4a); ³J_(CF)=9.1 Hz); 135.6 (C₂); 138.9(C_(4′)); 160.8 (C_(2a); ¹J_(CF)=247.5 Hz); 161.8 (NC═O); 163.0 (OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 3235 (NH); 1714 and 1683 (C═O);

EM (m/z): 367.37 (M^(•+)) 123 (M^(•+)−244.37; 100%).

7. Ester ethyl1-(4-cyanophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate(149b)

The derivative 149a was obtained with 80% of output in the form ofcrystals with fusion point at 171.0-172.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.41 (t, 3H, CH ₃, J=10.0 Hz);4.42 (q, 2H, CH ₂ J=10.0 Hz); 7.24 (m, 2H, H_(3a and 5a); J=10.0 and 5.0Hz); 7.56 (m, 1H, H_(4a); J=5.0 Hz); 7.58 (d, 2H, H_(2′) and H_(6′),J=10.0 Hz); 7.68 (s, 1H, H₂); 7.79 (d, 2H, H_(3′) and H_(5′), J=8.2 Hz);7.85 (t, 1H, H_(6a) J=10.0 Hz); 9.60 (d, 1H, NH, J=15.0 Hz);

¹³C RMN (125.0 MHz) (DMSO_(d6)/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 61.7(CH₂CH₃); 112.7 (C_(4′)); 117.7 (CN); 116.5 (C_(3a); ² J_(CF)=23.7 Hz);119.1 (C_(1a); ²J_(CF)=11.2 Hz); 123.0 (C₄); 124.4 (C_(2′) and C_(6′));125.1 (C_(5a); ⁴J_(CF)=2.5 Hz); 132.1 (C_(6a)); 132.8 (C₅); 133.8(C_(3′) and C_(5′)); 134.7 (C₂); 135.0 (C_(4a); ³ J_(CF) ⁼10.0 Hz);139.8 (C_(1′)); 160.9 (C_(2a); ¹J_(CF)=248.7 Hz); 161.6 (N{umlaut over(C)}═O, ³ J_(CF)=2.5 Hz); 163.0 (OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹: 3244 (NH); 2227 (CN); 1716 and 1661(C═O);

EM (m/z): 378.36 (M^(•+)); 123 (M^(•+)−255.36; 100%).

8. Ester ethyl1-(4-chlorophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate(149c)

The derivative 149c was obtained with 74% of output in the form ofcrystals with fusion point at 156.0-157.0° C.

¹H RMN (400.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.38 (t, 3H, CH ₃, J=10.0 Hz);4.39 (q, 2H, CH ₂ J=10.0 Hz); 7.22 (m, 2H, H_(3a and 5a); J=8.4; 6.4 and3.6 Hz); 7.37 (dd, 2H, H_(2′) and H_(6′), J=8.8 and 2.0 Hz); 7.43 (dd,2H, H_(3′) and H_(5′), J=9.2 and 2.4 Hz); 7.54 (dq, 1H, H_(4a); J=6.4and 3.6 Hz); 7.64 (s, 1H, H₂); 7.88 (t, 1H, H_(6a) J=8.0 and 2.0 Hz);9.27 (d, 1H, NH, J=15.0 Hz);

¹³C RMN (100.0 MHz) (DMSO_(d6)/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 61.0(CH₂CH₃); 116.4 (C_(3a); ²H_(CF)=24.5 Hz); 119.4 (C_(1a); ²J_(CF)=11.5Hz); 123.0 (C₄); 125.0 (C_(5a): ⁴J_(CF)=2.7 Hz); 125.4 (C_(2′) andC_(6′)); 129.9 (C_(3′) and C_(5′)); 132.1 (C_(6a)); 132.8 (C₅); 134.5(C_(4a); ³J_(CF)=10.0 Hz); 134.7 (C₂); 134.8 (C_(4′)); 139.8 (C_(1′));160.9 (C_(2a); ¹J_(CF)=248.4 Hz); 161.8 (NC═O, ³ J_(CF)=3.9 Hz); 162.9(OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 3266 (NH) 1770; 1664 (C═O);

EM (m/z): 387.79 (M^(•+)); 123 (M^(•+)−264.79; 100%).

9. Ester ethyl1-(3,5-dichlorophenyl)-5-[(2-fluoroben-zoic)amino]-1H-imidazole-4-carboxylate(149d)

The derivative 149d was obtained with 80% of output in the form ofcrystals with fusion point at 76.0-77.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.40 (t, 3H, C{umlaut over(H)}₃, J=7.5 Hz); 4.40 (q, 2H, CH ₂ J=7.0 Hz); 7.24 (m, 2H,H_(3a and 5a); J=8.5 and 3.5 Hz); 7.36 (d, 2H, H_(2′) and H_(6′), J=2.0Hz); 7.41 (d, 2H, H_(4′), J=2.0 Hz); 7.56 (dq, 1H, H_(4a); J=7.5 and 1.5Hz); 7.65 (s, 1H, H₂); 7.89 (t, 1H, H_(6a) J=7.5 and 6.5 Hz); 9.44 (d,1H, NH, J=13.0 Hz);

¹³C RMN (125.0 MHz) (DMSO_(d6)/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 61.7(CH₂CH₃); 116.4 (C_(3a); ²J_(CF)=23.7 Hz); 119.3 (C_(1a); ²J_(CF)=11.2Hz); 123.0 (C₄); 122.5 (C_(2′) and C_(6′)); 125.1 (C_(5a); ⁴J_(CF)=2.5Hz); 129.0 (C_(4′)); 135.1 (C_(3′) and C_(5′)); 132.0 (C_(6a)); 132.6(C₅); 134.7 (C₂); 134.8 (C_(4a); ³ J_(CF)=8.7 Hz); 137.6 (C_(1′)); 160.9(C_(2a); ¹J_(CF)=247.5 Hz); 161.9 (NC═O); 162.9 (OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 3549 (NH); 1725 and 1686 (C═O);

EM (m/z): 422.24 (M^(•+)); 123 (M^(•+)−299.24; 100%).

10. Ester ethyl1-(2,6-difluorophenyl)-5-[(2-fluoroben-zoic)amino]-1H-imidazole-4-carboxylate(149e)

The derivative 149e was obtained with 75% of output in the form oftransparent crystals with fusion point at 184.0° C.

¹H RMN (500.00 MHz; CDCl₃/Me₄Si) δ (ppm): 1.41 (t, 3H CH ₃, J=10.0 Hz);4.42 (q, 2H, CH ₂ J=10.0 Hz); 7.85 (t; 1H; H_(6a); J=10.0 and 5.0 Hz);7.08 (t, 2H, H_(3′) and H_(5′), J=10.0 and 5.0 Hz); 7.53 (dq, 1H,H_(4′), J=10.0 and 5.0 Hz); 7.19 (m, 2H, H_(3a) and H_(5a); J=10.0 and5.0 Hz); 7.40 (dq; 1H; H_(4a); J=12.0, 5.5 and 1.5 Hz); 7.57 (s, 1H,H₂); 9.57 (s, 1H, NH);

¹³C RMN (125.0 MHz) (CDCl₃/Me₄Si) δ (ppm): 14.3 (CH₂ CH₃); 61.0(CH₂CH₃); 114.0 (C_(1′); ²J_(CF)=16.0 Hz); 116.0 (C_(3a); ²J_(CF)=23.7Hz); 119.3 (C_(1a); ²J_(CF)=11.2 Hz); 121.7 (C₄); 122.6 (C_(3′) andC_(5′); ³J_(CF)=19.5 Hz); 124.0 (C_(5a); ⁴J_(CF)=2.5 Hz); 130.7 (C_(4′);³J_(CF)=10.0 Hz); 132.0 (C_(6a)); 134.7 (C_(4a); ³J_(CF)=8.7 Hz); 134.4(C₅); 135.8 (C₂); 157.2 (C_(2a); ¹J_(CF)=255.3 and ¹J_(CF)=3.7 Hz);160.8 (C_(2′) and C_(6′); ¹J_(CF)=247.5 Hz); 161.3 (NC═O); 163.1 (OC═O);

IV (tablet of KBr (1%)) ν (cm⁻¹): 3167 (NH); 1688 (C═O);

EM (m/z): 389.33 (M^(•+)); 123 (M^(•+)−266.33; 100%).

The invention hereby described, as the aspects approached must beconsidered as one of the possible concretizations. However, it must beclear that the invention is not limited to these concretizations andthat those with technical capacity shall notice that any particularcharacteristics introduced to it should be only understood as somethingthat was described in order to facilitate the understanding and cannotbe made without departing from the inventive concept described. Thelimiting characteristics of this invention are related to the claimsthat are part of this report.

The invention claimed is:
 1. AZOLE COMPOUNDS wherein the compounds1,2,3-triazole, or one of its salts, is represented by the generalformula VIII:

where: where X is “N” and the radicals of the triazole ring arerepresented by: R₁=CF₂R₆; R₆=R₁₀=alkyl; and where radical R_(n) can belocated in any one or in more than one of the carbon atoms of thearomatic ring, and is represented by a halogen.
 2. AZOLE COMPOUNDSaccording to claim 1 wherein the compounds 1,2,3-triazole are selectedamong: 1-(3-chlorophenyl)-4-difluoromethyl -1H-1,2,3-triazole; and1-(3,5-dichlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole; or one oftheir salts.
 3. AZOLE COMPOUNDS according to claim 1 wherein thecompounds 1,2,3-triazole are selected among:(AND)-4-chloride-N-((1-(4-chlorophenyl)-1H-1,2,3-triazole-4-il)methylene)benzenamine;and,(AND)-4-bromo-N-((1-(4-bromophenyl)-1H-1,2,3-triazole-4-il)methylene)benzenamine,or one of their salts.
 4. A PHARMACEUTICAL COMPOSITION comprising atleast one of the 1,2,3-triazole compounds, or one of their salts,represented by the general formula VIII:

where: where X is “N” and the radicals of the triazole ring arerepresented by: R₁=CF₂R₆; R₆=R₁₀=alkyl; and where radical R_(n) can belocated in any one or in more than one of the carbon atoms of thearomatic ring and is represented by a halogen, thus “n” can vary from 1to 5; and a pharmaceutically acceptable carrier.
 5. THE PHARMACEUTICALCOMPOSITION according to claim 4 wherein the compounds 1,2,3-triazoleare selected among:1-(3-chlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole; and1-(3,5-dichlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole; or one oftheir salts.
 6. THE PHARMACEUTICAL COMPOSITION according to claim 4wherein the compounds 1,2,3-triazole are selected among:(AND)-4-chloride-N-((1-(4-chlorophenyl)-1H-1,2,3-triazole-4-il)methylene)benzenamine; and,(AND)-4-bromo-N-((1-(4-bromophenyl)-1H-1,2,3-triazole-4-il)methylene)benzenamine, or one of their salts.
 7. A PHARMACEUTICALCOMPOSITION according to claim 4 wherein the composition is in thepharmaceutical form of solution, suspension, emulsion, ointment, cream,gel, tablet and/or capsule.
 8. THE PHARMACEUTICAL COMPOSITION accordingto claim 4 wherein the composition is in the pharmaceutical formulationfor oral, topical and/or injection form.
 9. A PHARMACEUTICALCOMPOSITION, comprising a therapeutically effective amount of thecompound of claim 1 and a pharmaceutically acceptable carrier.